MODIFICATION OF NATURAL HYDROPHILIC POLYMERS FOR USE IN PHARMACEUTICAL...

Ph.D. THESIS

I

MODIFICATION OF NATURAL HYDROPHILIC

POLYMERS FOR USE IN PHARMACEUTICAL

FORMULATIONS

By

Nedal Hamdan Mahmoud Daraghmeh

(B.Sc. Chemistry; M.Sc., Analytical Chemistry)

A thesis submitted in partial fulfilment of the requirements of the University of

Greenwich for the Degree of Doctor of Philosophy

November, 2012

School of Science

University of Greenwich,

Medway Campus,

Chatham Maritime,

Kent ME4 4TB, UK

DECLARATION

II N.H.M.Daraghmeh–PhD Thesis

DECLARATION

“I certify that this work has not been accepted in substance for any degree, and is not concurrently

being submitted for any purpose, other than that of the PhD thesis being studied at the University

of Greenwich. I also declare that this work is the result of my own investigations except where

otherwise identified by references and that I have not plagiarised another’s work”.

____________________________ (Mr N. H. M. Daraghmeh) (Candidate)

………………………………………………………………………………………………………..

Doctoral Supervisors

____________________________ (Prof. S. A. Leharne) (Academic supervisor)

_____________________________ (Prof. B. Z. Chowdhry (Academic supervisor)

_____________________________ (Dr A. Badwan (Industrial Supervisor)

11/08/2012

ACKNOWLEDGMENTS

III N.H.M.Daraghmeh–PhD Thesis

ACKNOWLEDGMENTS

Firstly, I would like to express my sincere gratitude to Prof. S. A. Leharne, Prof. B. Z. Chowdhry

and Dr Adnan Badwan for their steadfast support in my scientific studies.

I would also like to thank all my colleagues (particularly Dr. Mahmoud M.H. Al Omari and Dr

Iyad Rashid) at The Jordanian Pharmaceutical Manufacturing Co., for all their help and

encouragement in undertaking this endeavour.

My thanks to the Jordanian Pharmaceutical Manufacturing Co., Ltd, for financing this Ph.D. study.

Last, but certainly not least, I wish to express my heartfelt gratitude to my wife, and family for

their enduring support towards my studies.

ABSTRACT

IV N.H.M.Daraghmeh–PhD Thesis

ABSTRACT

MODIFICATION OF NATURAL HYDROPHILIC POLYMERS FOR USE IN PHARMACEUTICAL

FORMULATIONS

The introductory chapter of this doctoral thesis provides an overview of the salient properties of

pharmaceutical excipients, chitin, metal silicates and sugar alcohols in order to give a scientific

background/context to the research subject matter reported in subsequent chapter of the thesis.

When chitin is used in pharmaceutical formulations processing of chitin with metal silicates is

advantageous, from both an industrial and pharmaceutical perspective, compared to processing

using silicon dioxide. Unlike the use of acidic and basic reagents for the industrial preparation of

chitin-silica particles, co-precipitation of metal silicates is dependent upon a simple replacement

reaction between sodium silicate and metal chlorides. When co-precipitated onto chitin particles,

aluminum, magnesium, or calcium silicates result in non-hygroscopic, highly compactable, and

disintegrable compacts. Disintegration and hardness parameters for co-processed chitin compacts

were investigated and found to be independent of the particle size. Capillary action appears to be

the major contributor to both water uptake and the driving force for disintegration of compacts. The

good compaction and compression properties exhibited by the chitin–metal silicates were found to

be strongly dependent upon the type of metal silicate co-precipitated onto chitin. In addition, the

inherent binding and disintegration abilities of chitin–metal silicates are useful in pharmaceutical

applications when poorly compressible and/or highly non-polar drugs need to be formulated.

The influence of the lubricant magnesium stearate (MgSt) on the powder and tablet properties of

chitin-Mg silicate co-precipitate was examined and compared with lubricated Avicel® 200 and

Avicel-Mg silicate co-precipitate. Crushing strength and disintegration-time studies were

conducted in order to evaluate tablet properties at different compression pressures. Lubrication of

chitin-Mg silicate powder with MgSt was evaluated using a high speed rotary tablet press. The

compactability and disintegration time of chitin-Mg silicate are unaffected by the possible

deleterious action of up to 2% (w/w) MgSt. The deleterious effect of MgSt on Avicel® 200

compaction was found to be minimized when magnesium silicate was co-precipitated onto Avicel®

200. Lubrication of chitin-Mg silicate with MgSt does not enhance particle agglomeration, whereas

the opposite is the case for Avicel® 200; the foregoing was ascertained by measurements of the

fixed measured bulk density, constant powder porosity using Kawakita analysis and by the absence

ABSTRACT

V N.H.M.Daraghmeh–PhD Thesis

of variation in particle size distribution in the presence of up to 5% (w/w) MgSt. In the case of

chitin-Mg silicate tablets the ejection force was greatly reduced at a compression speed of

150,000 tablet/h at a MgSt concentration of 0.5% (w/w) when compared with the unlubricated

powder. The physical properties and drug dissolution profile of ibuprofen tablets were found to be

unaffected when chitin-Mg silicate was lubricated up to 5% (w/w) with MgSt. Optimal drug

dissolution was attained for gemfibrozil tablets using 3% (w/w) MgSt when compared to a

reference (LOPID® tablets).

A co-processed excipient was prepared from commercially available crystalline mannitol and

-chitin using direct compression as well as spray, wet and dry granulation. The effect of the ratio

of the two components, percentage of lubricant and particle size on the properties of the prepared

co-processed excipient has been investigated. -Chitin forms non-hygroscopic, highly

compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction

properties of the co-processed mannitol-chitin mixture were found to be dependent upon the

quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal

physicochemical properties of the excipient, from a manufacturing perspective, were obtained

using a co-processed mannitol-chitin (2:8 w/w) mixture prepared by wet granulation (Cop-MC).

Disintegration time, crushing strength and friability of tablets produced by Cop-MC, using

magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared

granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful

for the formulation of poorly compressible, low and high strength active pharmaceutical

ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as

a valuable industrial pharmaceutical excipient.

The preparation and characterization of the performance of a novel excipient for use in the

development of oro-dispersible tablets (ODT) has also been undertaken. The excipient consists of

α-chitin and crystalline mannitol. The physical properties (disintegration and wetting times,

crushing force and friability) of the ODTs produced depend on the ratio of chitin and mannitol, in

addition to the processing techniques used for excipient preparation. The excipient with optimal

physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w) produced by roll

compaction (Cop-CM). Differential scanning calorimetry (DSC), Fourier-transform infrared

(FT-IR), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) techniques

were used to characterize the Cop-CM, in addition to characterization of its powder and ODT

dosage forms. The effect of particle size distribution of the Cop-CM was investigated and found to

ABSTRACT

VI N.H.M.Daraghmeh–PhD Thesis

have no significant influence on the overall tablet physical properties. The compressibility

parameter (a) for Cop-CM was calculated from a Kawakita plot and found to be significantly

higher (0.661) than that of mannitol (0.576) due to the presence of the highly compressible chitin

(0.818). Montelukast sodium and domperidone ODTs, produced using Cop-CM, displayed the

required physicochemical properties. The exceptional binding, fast wetting and super-

disintegration properties of Cop-CM, in comparison with commercially available co-processed

ODT excipients, results in a unique multi-functional base which can successfully be used in the

formulation of oro-dispersible and fast immediate release tablets.

N. H. M. Daraghmeh [B.Sc.; M.Sc.]

ABSTRACT

VII N.H.M.Daraghmeh–PhD Thesis

DEDICATION

This thesis is dedicated to my wife:

HALA NAZZAL (B.Sc.; M.Sc.)

My children:

BARA’A, MOHAMMAD & BASHAR

And my parents

ABSTRACT

VIII N.H.M.Daraghmeh–PhD Thesis

CONTENTS

TITLE PAGE I

DECLARATION II

ACKNOWLEDGMENTS III

ABSTRACT IV

DEDICATION VII

CONTENTS VIII

Publications/Conference Presentations X

List of Figures XII

List of Tables XVI

Abbreviations XVIII

1. Introduction 1

1.1. Pharmaceutical Excipients 1

1.2. Preparation Techniques for Solid Dosage Forms 4

1.3. Co-processed Excipients 10

1.4. Special Types of Excipients (Oro-dissolving Tablets) 23

1.5. Chitin: the Solid Dosage Form Excipient 27

1.6. Synthetic Metal Silicates 46

1.7. Sugar Alcohols 61

1.8. Project: Hypothesis, Aims and Work Plan 66

1.9. References 68

2. Characterization of Chitin–Metal Silicates as Binding Super-Disintegrants 74

2.1. Introductin 74

2.2. Experimental 76

2.3. Results and Discussion 82

2.4. Conclusions 99

2.5. References 100

3. Characterization of the Impact of Magnesium Stearate Lubrication on the

Tableting Properties of Chitin-Mg Silicate as a Superdisintegrating Binder when

Compared to Avicel® 200 104

3.1. Introduction 104



ABSTRACT

IX N.H.M.Daraghmeh–PhD Thesis

3.4. Conclusions 131

3.5. References 132

4. Preparation and Characterization of a Novel Co-Processed Excipient of Chitin

and Crystalline Mannitol 136





4.5. References 168

5. A Novel Oro-dispersible Tablet Base: Characterization and Performance 173





5.5. References 203

6. Summary and Future Work 207

6.1. Summary 207

6.2. Future Work 210

ABSTRACT

X N.H.M.Daraghmeh–PhD Thesis

Publications/Conference Presentations

Published Reviews in Monographs

(1) “Chitin”, Nedal H. Daraghmeh, Babur Z. Chowdhry, Stephen A. Leharne, Mahmoud M. Al

Omari, andAdnan A. Badwan: in Profiles of Drug Substances, Excipients, and Related

Methodology, 36, 35-102, 2011; Ed: H. G. Brittain (Elsevier Inc.)

(2) “Magnesium Silicate”, Iyad Rashid, Nedal H. Daraghmeh, Mahmoud M. Al Omari, Babur Z.

Chowdhry, Stephen A. Leharne, Hamdallah A. Hodali, and Adnan A. Badwan, in: Profiles of Drug

Substances, Excipients, and Related Methodology, 36, 241-285, 2011; Ed: H. G. Brittain, (Elsevier

Inc.).

Published Research Articles

(1) “Characterization of Chitin-Metal Silicates as Binding Superdisintegrants”, Iyad Rashid, Nedal

Daraghmeh, Mayyas Al-Remawi, Stephen A. Leharne, Babur Z. Chowdhry, Adnan Badwan,

Journal of Pharmaceutical Sciences, 98 (12), 4887–4901, 2009 (Chapter 2).

(2) “Characterization of the Impact of Magnesium Stearate Lubrication on the Tableting Properties

of Chitin-Mg Silicate as a Superdisintegrating Binder When Compared to Avicel® 200”, Iyad

Rashid, Nedal Daraghmeh, Mayyas Al-Remawi, Stephen A. Leharne, Babur Z. Chowdhry, Adnan

Badwan, Powder Technology, 203 (3), 0 609-619, 2010 (Chapter 3).

(3) “Preparation and Characterization of a Novel Co-Processed Excipient of Chitin and Crystalline

Mannitol”, Nedal Daraghmeh, Iyad Rashid, Mahmoud M. H. Al Omari, Stephen A. Leharne,

Babur Z. Chowdhry, and Adnan Badwan, AAPS Pharm. Sci. Tech. 11 (4) 1558-1571, 2010

(Chapter 4).

Research Manuscripts Submitted

(1)“A Novel Oro-Dispersible Tablet Base: Characterization and Performance”, Nedal Daraghmeh,

Babur Z. Chowdhry, Stephen A. Leharne, Mahmoud M.H. Al Omari, Adnan A. Badwan,

Submitted: J. Pharm. Sci., (2012) (Chapter 5).

Manuscripts in Preparation (2012)

(1) “Chitin the Pharmaceutical Disintegrant: A Review (Polymers)

(2) “Chitin/Magnesium Silicate Co-Precipitate as a Pharmaceutical Formulation Aid for

Enhancement of Drug Properties” (AAPS PharmSciTech)

ABSTRACT

XI N.H.M.Daraghmeh–PhD Thesis

Conference Presentations (Posters)

(1) “Preparation and Characterization of a Novel Co-Processed Excipient of Chitin and Crystalline

Mannitol”

5th

International Granulation Workshop, Lausanne, Switzerland: 20-22 June, 2011 and

11th

Eurasia Conference on Chemical Sciences: 6-10 October, 2010; the Dead Sea–Jordan

(2) “Characterization of Chitin-Metal Silicates as Binding Superdisintegrants”.

22nd

of December, 2009; University of Jordan.

(This poster won the Hisham Hijjawi award for Applied Sciences (Industry & Energy Sector))

(3) “The Effect of Metal Silicates on the Binding and Disintegration Properties of Chitin”

(4) “Chitin/Magnesium Silicate Co-Precipitate as a Pharmaceutical Formulation Aid for

Enhancement of Drug Properties”

Posters 3 and 4 were presented at Excipientfest Europe: 17–18 June, 2008; Cork, Ireland.

LIST OF FIGURES

XII N.H.M.Daraghmeh–PhD Thesis

LIST OF FIGURES

Figure 1.1 Comparison of steps involved in the different processing techniques of solid

dosage form preparations 6

Figure 1.2 Co-processing methodology 15

Figure 1.3 A) Material classification on the basis of their deformation behavior in the

presence of applied mechanical force, B) stages involved in compression (I – III)

and decompression 17

Figure 1.4 Mechanism of disintegration of ODTs 23

Figure 1.5 Chemical structure of chitin showing its monomer: N-acetyl-D-glucosamine 28

Figure 1.6 Biosynthesis of chitin 30

Figure 1.7 Scheme for the deacetylation of chitin 32

Figure 1.8 Mechanisms for the acid hydrolysis of chitin 33

Figure 1.9 Enzymatic hydrolysis of chitin and chitosan into their monomers 33

Figure 1.10 SEM images of α-chitin at magnifications of (A) x160 and (B) x1600 36

Figure 1.11 Modes of hydrogen bonding in (i) α-chitin: (a) intra-chain C(3') OH···OC(5)

bond; (b) intra-chain C(6'1)OH···O=C(71) bond; (c) inter-chain

C(6'1)O···HOC(62) bond; (d) inter-chain C(21)NH···O=C(73) and (ii) -chitin:

(a) intra-chain C(3')OH···OC(5) bond; (b) inter-chain C(21)NH···O=C(73) bond

and C(6'1)OH···O=C(73) bond (ac plane projection); (c) inter-chain

C(21)NH···O=C(73) bond (ab plane projection) 38

Figure 1.12 A) Relationship between tablet hardness and applied compression pressure

B) relationship between the tablet hardness and concentration of excipient used,

C) relationship between tablet disintegration time and concentration of excipient

(x: disintegration was not completed within 60 min) 42-43

Figure 1.13 The relationship between the tablet hardness and excipient concentration 44

Figure 1.14 Effect of compression pressure on the crushing strength of chitin, chitosan and

direct-compressed reference tablets 45

Figure 1.15 Molecular structure of magnesium silicate 47

Figure 1.16 Concentration of Mg2

ions, in deionized water, as a function of sodium silicate

concentration (pH 8.5) 48

Figure 1.17 Conditional solubility product of magnesium silicate as a function of pH for an

initial ion concentration of 1 mM 51

Figure 1.18 Schematic of the functional groups on the surface of magnesium silicate 52

Figure 1.19 SEM photograph of magnesium silicate (magnification = 100 m) 54

Figure 1.20 Preparation procedure for synthetic amorphous metal silicates (wet method) 55

Figure 1.21 Chemical structure of mannitol powder 62

Figure 1.22 SEM images of a) granular mannitol, b) mannitol powder and c) spray dried

mannitol 62

Figure 1.23 The aqueous solubility of mannitol versus other excipients 63

LIST OF FIGURES

XIII N.H.M.Daraghmeh–PhD Thesis

Figure 1.24 Tablet compression profiles of different grades of mannitol 63

Figure 1.25 Friability versus compression profile for different grades of mannitol 64

Figure 1.26 Moisture sorption profiles of different sugar alcohols at 20°C 64

Figure 2.1 FT-IR of Al, Mg, Ca silicates prepared by precipitation of the metal silicates via

a replacement reaction of sodium metasilicate with the metal chlorides 83

Figure 2.2 FTIR spectra for chitin, chitin-metal (Al, Mg, Ca) silicate co-precipitates, and

chitin-Mg silicate physical mixture 84

Figure 2.3 XRPD spectra for Al, Mg, Ca silicate precipitates 86

Figure 2.4 XRPD spectra for chitin-metal (Al, Mg, Ca) silicate co precipitates, chitin Mg

silicate physical mixture, and chitin 87

Figure 2.5 SEM of chitin (A), chitin-Mg silicate co-precipitate (B) and (C) 88

Figure 2.6 Water penetration rate of chitin-Mg silicate and Avicel® 200 as a function of

particle size (primary axis). Hygroscopicity of chitin-Mg silicate co precipitate

performed using standard salt solutions of different humidity conditions stored

inside desiccators at room temperature for 1 week (secondary axis). Error bars

presented as ± RSD. 90

Figure 2.7 Hardness and disintegration time as a function of compression force for different

particle size of chitin-Mg silicate co-precipitate 92

Figure 2.8 Hardness and disintegration time as a function of chitin-metal (Al, Mg, and Ca)

silicate content. Tablets were 12 mm in diameter and 400 mg weight 94

Figure 2.9 Kawakita plots for different concentrations of Mg silicate in the chitin-Mg

silicate co-precipitate. Tablets were 12 mm in diameter and 400 mg in weight 95

Figure 2.10 Kawakita plot for chitin-metal (Al, Mg, Ca) silicate co precipitates. Tablets were

12 mm in diameter and 400 mg in weight 96

Figure 3.1 Effect of MgSt concentration on tablet crushing strength of chitin-Mg silicate,

Avicel®200, calcium hydrogen orthophosphate, and Avicel-Mg silicate

co-precipitates at different compression pressures. Tablets, 12 mm in diameter

and weighing 400 mg each were used. A, B, C, and D represent compression

pressures of 156, 182, 208, 234 MPa, respectively 113

Figure 3.2 Effect of MgSt concentration on the disintegration time of chitin-Mg silicate,

Avicel® 200, and Avicel-Mg silicate tablets. Tablets were 12 mm in diameter

and 400 mg in weight, compressed to reach a fixed crushing strength value of

0.6 MPa 114

Figure 3.3 Kawakita plots for un-lubricated (0% w/w) and lubricated (1%, 5% w/w) chitin-

Mg silicate with MgSt (MgSt). Tablets were 12 mm in diameter and 400 mg in

weight 116

Figure 3.4 Kawakita plots for un-lubricated (0% w/w) and lubricated (1%, 5% w/w)

Avicel® 200 with MgSt (MgSt). Tablets were 12 mm in diameter and 400 mg in

weight 118

Figure 3.5 SEMs of un-lubricated chitin (A), unlubricated chitin-Mg silicate (B), lubricated

particles of chitin-Mg silicate up to 5% (w/w) MgSt (C), unlubricated Avicel®

200 (D), and lubricated Avicel® 200 up to 5% (w/w) MgSt (E) 127

LIST OF FIGURES

XIV N.H.M.Daraghmeh–PhD Thesis

Figure 3.6 Dissolution profiles for ibuprofen (400 mg strength) tablets formulated with un-

lubricated and lubricated (1% and 5%, w/w) chitin-Mg silicate (CMS), Avicel®,

and Avicel-Mg silicate (AMS) using physical mixing and direct compression.

MgSt was used as the lubricant. Tablets (700 mg) were 13 mm in diameter and

compressed at 182 MPa. Tablet crushing strength values are included in the

legend for each specific powder 129

Figure 3.7 Dissolution profile of gemfibrozil (600 mg strength) tablets formulated with

chitin-Mg silicate by physical mixing and direct compression. The lubricant

(MgSt) concentration was 3% (w/w). Tablets (850 mg) were 13 mm in diameter

and, compressed at 182 MPa. Lopid tablets (600 mg strength and 850 mg

weight) were used as a reference 130

Figure 4.1 Plots of the physical properties (crushing strength, disintegration time and

friability) of the co-processed mannitol-chitin mixture prepared by different

granulation techniques versus the amount of magnesium stearate added 149

Figure 4.2 SEM images of Cop-MC lubricated with (a) 0.5% and (b) 3.0% (w/w)

magnesium stearate; Avicel HFE 102 powder lubricated with (c) 0.5% and (d)

3.0% (w/w) magnesium stearate 150

Figure 4.3 FT-IR spectra of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-chitin

(2:8, w/w), and (d) Cop-MC 151

Figure 4.4 XRPD profiles of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-

chitin (2:8, w/w), and (d) Cop-MC 152

Figure 4.5 DSC thermograms of (a) chitin, (b) mannitol, (c) treated mannitol, (d) non

treated physical mixture of mannitol-chitin (2:8, w/w), (e) treated physical

mixture of mannitol-chitin (2:8, w/w) and (f) Cop-MC 153

Figure 4.6 SEM images of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-chitin

(2:8, w/w), (d) Cop-MC and (e) Avicel HFE 102 154

Figure 4.7 The water gained by Cop-MC and Avicel HFE 102 kept in an open container at

different relative humidities and 20oC 155

Figure 4.8 Effect of Cop-MC particle size on tablet crushing strength, disintegration time

and friability. The tablets were 9 mm in diameter and 180 mg in weight. All

samples were lubricated with 0.5% (w/w) magnesium stearate 157

Figure 4.9 Kawakita plot for mannitol:chitin (20:80) Prepared by a wet granulation

procedure. Tablets were 12 mm in diameter and 400 mg in weight 158

Figure 4.10 DSC scans of methyldopa 250 mg tablets (Formula 4) (a) after 6 months at

40oC/75% RH–close amber glass bottles, (b) after 6 months at 40

oC/75% RH–

open amber glass bottles, (c) initial analysis, (d) reference formula (without

active ingredient) at 40oC/75% RH–close amber glass bottles, (e) reference

formula (without active ingredient) at 40oC/75% RH–open glass amber bottles,

(f) methyldopa at 40oC/75% RH–close amber glass bottles, (g) methyldopa at

40oC /75% RH–open amber glass bottles and methyldopa initial analysis 163

Figure 4.11 HPLC chromatograms of (A) methyldopa, (B) methyldopa 250 mg tablets

(Formula 4) and (C) aldomet 250 mg tablets. Where (a) is the initial

chromatogram (no incubation), and (b)/(c) after 3 and 6 months incubation at

40oC/75% RH, respectively in closed containers 166

LIST OF FIGURES

XV N.H.M.Daraghmeh–PhD Thesis

Figure 5.1 Plot of the crushing force (N) versus (a) disintegration time, (b) friability, and (c)

wetting time for compacted mixtures prepared from different ratio of chitin and

mannitol (1:9, 2:8, and 3:7 w/w). Tablets are 10 mm in diameter and 250 mg in

weight. All powders were lubricated using 1% (w/w) sodium stearyl fumarate 183

Figure 5.2 FT-IR spectra of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-chitin

(2:8, w/w), and (d) Cop-CM 184

Figure 5.3 XRPD profiles of (a) mannitol, (b) chitin, (c) physical mixture of chitin-mannitol

(2:8, w/w), and (d) Cop-CM 185


treated physical mixture of mannitol-chitin (2:8, w/w), (e) treated physical

mixture of chitin-mannitol (2:8, w/w) and (f) Cop-CM 186

Figure 5.5 SEM images of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-chitin

(2:8, w/w), and (d) Cop-CM 187

Figure 5.6 The water uptake by Cop-CM in comparison with some commercially available

ODT bases after incubation at 25oC and different relative humidity (a) for 2

weeks and (b) after equilibrium at 25oC/45% relative humidity for further 1 day 190

Figure 5.7 Plot of the crushing force (N) versus (a) disintegration time, (b) friability, and (c)

wetting time for tablets prepared from Cop-CM powders passed through either

710 m or 1000 m sieves in comparison with commercially available bases.

The tablets were 10 mm in diameter and 250 mg in weight. All samples were

lubricated with 1% (w/w) sodium stearyl fumarate 192

Figure 5.8 Kawakita plot for Cop-CM prepared by a roll compaction procedure. Tablets

were 12 mm in diameter and 400 mg in weight 197

Figure 5.9 Relationship between tablet crushing force and disintegration time at different

Cop-CM:metronidazole ratios using a treated physical mixture of chitin and

mannitol as reference. Data are represented as mean of n = 10 199

LIST OF TABLES

XVI N.H.M.Daraghmeh–PhD Thesis

LIST OF TABLES

Table 1.1 Classification of excipients according to their function 2

Table 1.2 Dosage form parameters affected by excipients 3

Table 1.3 Excipients commonly used in solid dosage form formulations 4

Table 1.4 Methods used to prepare direct compression excipients 8

Table 1.5 Critical issues, advantages and limitations of direct compression process 9

Table 1.6 Examples of some commercially available direct compression excipients 10

Table 1.7 Commercially marketed co-processed direct compression excipients 12-13

Table 1.8 Material classification according to their response to applied mechanical force 16

Table 1.9 Particle properties influencing excipient functionality 19

Table 1.10 Parameters involved in the evaluation of co-processed and direct compression

excipients 21-22

Table 1.11 Technologies used in ODT preparations 25

Table 1.12 Commonly used excipients in ODT preparations 26

Table 1.13 Methods for the preparation of chitin 29

Table 1.14 Methods of deacetylation of chitin to form chitosan 31

Table 1.15 Solubility of -chitin in different solvents and solvent mixtures performed at

room temperature 34

Table 1.16 Solubility of -chitin in various calcium and magnesium salt-alcohol solutions 35

Table 1.17 The solubility of - and -chitins and structurally related compounds in a

saturated CaCl2.2H2O-methanol solvent system 36

Table 1.18 Crystallographic parameters for α-and β-chitins 37

Table 1.19 Estimated global market prices of some pharmaceutical excipients 39

Table 1.20 Examples of applications of chitin and its derivatives 41

Table 1.21 Compression and compaction properties of chitin, chitosan and direct

compression reference excipients 45

Table 1.22 Acceptance criteria of content of magnesium oxide and silicon dioxide in

magnesium silicate 47

Table 1.23 The total amount of Mg and Si dissolved (mg/50 mL) in various solutions at

25oC 50

Table 1.24 Physicochemical properties of unmodified and modified magnesium silicates 53

Table 1.25 Physicochemical properties of unmodified magnesium silicate and magnesium

silicate modified with silane coupling agents 53

Table 1.26 Composition of synthetic calcium silicate and synthetic aluminium sodium

silicate 54

Table 1.27 Physicochemical properties and toxicological profile of some synthetic

amorphous silicates products 57-58

LIST OF TABLES

XVII N.H.M.Daraghmeh–PhD Thesis

Table 1.28 Applications of metal silicates in various industries 59-60

Table 1.29 Comparison of sugars and sugar alcohols 61

Table 2.1 Composition of paracetamol, metformin HCl, and mefenamic acid tablets

formulations 81

Table 2.2 Kawakita parameters for different concentrations of Mg silicate precipitates in

the chitin-Mg silicate co precipitate and for chitin-metal (Al, Mg, Ca) silicate co

precipitates 97

Table 2.3 Hardness, disintegration, and dissolution results for the paracetamol, metformin

HCl, and mefenamic acid tablets formulations 98

Table 3.1 Kawakita parameters for lubricated (with MgSt) and un-lubricated chitin-Mg

silicate and Avicel® 200 117

Table 3.2 Physical parameters of lubricated, un-lubricated chitin, chitin-Mg silicate,

Avicel® 200 and Avicel-Mg silicate powders 119

Table 3.3 Effect of Fette P2100 tablet press compression speed on unlubricated and lubricated

(up to 0.5% w/w with MgSt) ejection force for chitin-Mg silicate, stickiness to the

punches, tablet crushing strength, disintegration time, appearance of cracks and tablet

weight. Tablets were 12 mm circular 128

Table 4.1 Kawakita parameters 158

Table 4.2 Physical properties of rosuvastatin 20 mg, -methyldopa 250 mg and amlodipine

10 mg tablets 162

Table 4.3 Stability data for -methyldopa 250 mg film coated tablets at 40oC/75% RH 164

Table 5.1 The physical properties of Cop-CM 188

Table 5.2 Function and composition of used ODT excipients 194

Table 5.3 Kawakita parameters for mannitol, chitin and Cop-CM 197

Table 5.4 Composition and physical properties of Monte and Domp ODT 200

Table 5.5 Stability data for Monte and Domp tablets 201

ABBREVIATIONS

XVIII N.H.M.Daraghmeh –PhD Thesis

ABBREVIATIONS

Symbol Description

NHCOCH3 Acetamide

HCOOH Acetic acid

API Active pharmaceutical ingredient

ATP Adenosine triphosphate

α- Alpha-

UTP -D-hexose-1- phosphate uridylyltransferase

AlCl3 Aluminium chloride

Al2(SiO3)3 Aluminum silicate

NH2 Amine

NH4NO3 Ammonium nitrate

Å Angstrom

BD Bulk density

β- Beta-

Cop-MC Co-processed mannitol-chitin (2:8 w/w) mixture prepared by wet

granulation

Cop-CM Co-processed chitin-mannitol (2:8 w/w) mixture produced by roll

compaction

CaCO3 Calcium carbonate

CaCl2 Calcium chloride

CaCl22H2O Calcium chloride dihydrate

Ca(SCN)2.4H2O Calcium cyanate tetrahydrate

Ca(NO3)2.4H2O Calcium nitrate tetrahydrate

CaSiO3 Calcium silicate

CO2 Carbon dioxide

C=O Carbonyl

(C8H31NO5)n Chitin

CSD Colloidal silicon dioxide

Crospovidone Cross-linked polymer of N-vinyl-2-pyrrolidinone

Da Dalton

DBCP Dibasic calcium phosphate

DBCH Dibutyrylchitin

DSC Differential scanning calorimetry

DMAc/LiCl N,N-Dimethylacetamide/Lithium chloride

DMF N,N-Dimethylformamide

DC Direct compression

Domp Domperidone

EP European patent

EDTA Ethylene di-amine tetra-acetic acid

FDA Food and Drug Administration

FCC Food Chemical Codex

FTIR Fourier- transform infra-red

- Gamma-

GRAS Generally recognized as safe

HPLC High performance liquid chromatography

HCl Hydrochloric acid

HF Hydrofluoric acid

H2O2 Hydrogen peroxide

OH- Hydroxyl

HPC Hydroxypropylcellulose

ABBREVIATIONS

XIX N.H.M.Daraghmeh –PhD Thesis

Symbol Description HPMC Hydroxypropylmethylcellulose

ICH International conference of harmonization

IPEC International Pharmaceutical Excipients Council

JECFA The Joint Food and Agriculture Organization/World Health Organization

Expert Committee on Food Additives

LOQ Limit of quantitation

MgCl2 Magnesium chloride

MgCl2.6H2O Magnesium chloride hexahydrate

Mg(NO3)2.6H2O Magnesium nitrate hexahydrate

MgO Magnesium oxide

MgSiO3 Magnesium silicate

MgSt Magnesium stearate

LD50 Median toxic dose; “Lethal Dose, 50%”

MCC Microcrystalline cellulose

Monte Montelukast sodium

NF National Formulary

NMR Nuclear magnetic resonance

ODT Oro-dissolving tablets/Oro-disintegrating tablets

O-3 MD O-3-Methylmethyldopa impurity

KCl Potassium chloride

KOH Potassium hydroxide

PGS Pregelatinized starch

RH Relative impurity

RSD Relative standard deviation

RC Roll compaction

RSC Rosuvastatin calcium

SEM Scanning electron microscope

SMCC Silicified microcrystalline cellulose

SiO2 Silicon dioxide

NaCl Sodium chloride

NaOH Sodium hydroxide

Na2HPO4.12H2O Sodium hydrogen phosphate dodecahydrate

Na2SiO3 Sodium metasilicate

H2SO4 /H3PO4 Sulphuric acid/Phosphoric acid

TD Tapped density

3D Three dimensional

UV Ultra-violet

USP United States Pharmacopiea

UTM Universal testing machine

UDP-N-acetylglucosamine Uridinediphosphate-N-acetyl-glucosamine

V Voltage WG Wet granulation

WHO/FAO World Health Organization/Food and Agriculture Organization of the

United Nations

XRPD X-Ray Powder Diffraction Spectroscopy

CHAPTER ONE INTRODUCTION

1 N.H.M.Daraghmeh–PhD Thesis

Introduction

1.1 Pharmaceutical Excipients

The International Pharmaceutical Excipients Council (IPEC) defines excipients as:

“Substances, other than the active pharmaceutical ingredient (API) in finished dosage

form, which have been appropriately evaluated for safety and are included in a drug

delivery system to either aid the processing or to aid manufacture, protect, support,

enhance stability, bioavailability or patient acceptability, assist in product

identification, or enhance any other attributes of the overall safety and effectiveness

of the drug delivery system during storage or use” [1]. Ideally, excipients should not

produce any pharmacological action, or adversely impact drug product quality, safety,

or efficacy [2]. Recently, researchers have reached the conclusion that excipients are

not inactive and have a substantial impact on the manufacture, quality, safety, and

efficacy of the API in a dosage form [3]. Furthermore, variability in the performance

of an excipient (both batch to batch within a single manufacturer as well as between

batches from different manufacturers) is a key determinant of dosage form

performance and consistency. Excipients are now known to have numerous, defined

functional roles in pharmaceutical dosage forms [3]. These include:

modulating the solubility and bioavailability of the API,

enhancing the stability of the API in the dosage form,

contributing to the maintenance of a preferred polymorphic form or

conformation of the API(s),

pH and osmotic pressure modifiers,

acting as antioxidants, emulsifying agents, aerosol propellants, tablet

binders and tablet disintegrants, and

preventing aggregation or dissociation.

Excipients can be obtained from different sources (natural, animal, vegetable, semi-

synthetic, or synthetic) using different production technologies to be used for different

functions and applications [3, 4]. Excipients are classified into different categories

based on their function (e.g., diluent/filler, binder, disintegrant, glidant, lubricant, etc.)

and they normally fulfill various performance characteristics and specifications (e.g., bulk

density, particle size distribution, surface area, polymorphic form, water content etc.)

depending on their uses in formulations, manufacturing processes, and the intended



dosage form [4, 5, 6]. The definitions of different excipient categories used in solid

dosage form formulations are illustrated in Table 1.1.

Table 1.1 Classification of excipients according to their functions.

Excipient Function Definition

Fillers/Diluents

Fillers are added to increase the bulk of the formulation i.e. fillers fill out the size

of a tablet or capsule, making it practical to produce and convenient for the

consumer to use. Fillers make it possible for the final product to possess the

proper volume for patient handling.

Binders

Some pharmaceutical ingredients require a binder for tabletting. This provides the

cohesiveness necessary for bonding during tablet compression. Binders are usually

starches, sugars, cellulose or a modified cellulose (such as microcrystalline cellulose,

hydroxypropyl cellulose), lactose, or sugar alcohols like xylitol, sorbitol or maltitol.

Binders can be used in dry (solid state) form or dissolved in solution.

Disintegrants

Usually added for the purpose of ensuring that compressed tablets break apart when

placed in an aqueous medium.

Lubricants

Prevent ingredients from clumping together and from sticking to the tablet punches or

capsule filling machine. Lubricants also ensure that tablet formation and ejection can

occur with low friction between the solid and die wall. Common minerals like talc or

silica, and fats, metal stearate like magnesium stearate or stearic acid are the most

frequently used lubricants in tablets or hard gelatine capsules.

Glidants

Glidants are used to promote powder flow by reducing inter-particle friction and

cohesion. Glidants, in some cases, occur in solution form due to the weight variation

problems during tablet compression and capsule filling as a result of improving the

powder flowability. Generally, materials that are good glidants are poor lubricants.

Excipients play a pivotal role in the processing, stability, safety, and performance of

solid dosage forms. Therefore, the critical excipient properties that can influence

product performance need to be evaluated and controlled to ensure that consistent

product performance is achieved throughout the product’s life cycle [7, 8]. An

overview of some dosage form parameters affected by excipients is given in

Table 1.2.

http://en.wikipedia.org/wiki/Starch

http://en.wikipedia.org/wiki/Sugar

http://en.wikipedia.org/wiki/Cellulose

http://en.wikipedia.org/w/index.php?title=Microcrystalline_cellulose&action=edit&redlink=1

http://en.wikipedia.org/wiki/Hydroxypropyl_cellulose

http://en.wikipedia.org/wiki/Lactose

http://en.wikipedia.org/wiki/Xylitol

http://en.wikipedia.org/wiki/Sorbitol

http://en.wikipedia.org/wiki/Maltitol

http://en.wikipedia.org/wiki/Lubricant

http://en.wikipedia.org/w/index.php?title=Capsule_filling_machine&action=edit&redlink=1

http://en.wikipedia.org/wiki/Friction

http://en.wikipedia.org/wiki/Talc

http://en.wikipedia.org/wiki/Silica

http://en.wikipedia.org/wiki/Fat

http://en.wikipedia.org/wiki/Magnesium_stearate

http://en.wikipedia.org/wiki/Stearic_acid



Table 1.2 Dosage form parameters affected by excipients.

Dosage form parameter Effect of excipients

Stability Residual moisture content/adsorbed moisture on excipient surface

protects API from hydrolytic degradation.

Processability Surface area, surface free energy, crystal defects, and deformation

potential affect compressibility and machine ability for high speed

tabletting machines with reduced compression dwell times.

Particle size distribution and shape affect flow properties, efficiency

of dry mixing processes, and segregation potential.

Compressibility, flowability, and dilution potential affect the choice

of direct compression as a manufacturing process.

Performance Cohesive and adhesive properties, surface free energy, and water

uptake behavior affect disintegration and dissolution behavior.

Generally, pharmaceutical excipients have to meet special requirements including [4]:

physiological inertness,

acceptance by regulatory authorities,

physical and chemical stability,

commercial availability at pharmaceutical grade and standards,

being relatively inexpensive, and

their approval as a food additive if it is intended for use in dietary supplements

and vitamin products.

Table 1.3 lists some of the commercially available excipients, exploited for their

different functionalities, commonly used in solid dosage formulations [9].



Table 1.3 Commonly used excipients in solid dosage formulations.

Material Trade name Company Function

Mannitol Pearlitol Roquette/ USA Filler

Lactose monohydrate Pharmatose DMV Pharma / Netherlands Filler

Microcrystalline cellulose Avicel PH FMC Biopolymer / USA Filler

Starch C*PharmGel Cerestar / France Filler/Disintegrant

Croscarmelose sodium Ac-Di-Sol FMC Biopolymer / USA Disintegrant

Sodium starch glycolate Explotab JRS Pharma LP / USA Disintegrant

Cross-linked polyvinylpyrollidone Polyplasdone XL ISP / USA Disintegrant

Pregelatinized starch Starch 1500 Colorcon / UK Disintegrant/Binder

Low substituted

hydroxypropylcellulose

L-HPC Shin-Etsu Chemical / Japan Disintegrant/Binder/

Filler

Hydroxypropylcellulose Klucel Aqualon /USA Binder

Poly(vinylpyrollidone) Kollidon PASF corp./USA Binder

Sodium stearyl fumarate Pruv JRS Pharma LP/USA Lubricant

Magnesium stearate Magnesium Stearate Mallinckrodt Baker/ USA Lubricant

Purified talc Altalc Luzenac America/USA Lubricant/Glidant

Colloidal silicon dioxide Aerosil Degussa Ltd / UK Glidant

1.2 Preparation Techniques for Solid Dosage Forms

Development of solid dosage forms, more specifically tablets, involves major

alternative processing methodologies including wet granulation (low shear wet

granulation, high shear wet granulation or fluid-bed granulation), dry granulation

(slugging or roller compaction) or direct compression (DC) [8, 10]. The detailed

processing steps involved in each of the three processing methods are explained in

Figure 1.1 [4]. These processing methods share the following common problems [8]:

product weight variation due to poor flow properties,

problems in content uniformity during mixing, due to wide differences in

density and particle size distribution,

loss of excipient compressibility due to wet granulation and repeated

compaction cycles in dry granulation, or excessive usage of lubricants and

poorly compressible ingredients in the formulation, and

poor disintegration of product due to excessive addition of binders.



The use of high speed tabletting machines and the increasing shift in the processing of

tablets towards direct compression have, together, led to aggravating these problems.

1.2.1 Wet Granulation [4, 11]

Granulation is the process of collecting particles together by creating bonds between them.

When the required homogeneity, compactibility or flowability of powder cannot be

obtained by simple mixing, the ingredients must be granulated prior to compression. There

are several reasons for using granulation processes (wet / dry) including the following:

improving powder flowability,

improving content uniformity of APIs in dosage form to assure consistency of dosing,

improving the bioavailability of some APIs,

taste masking of poor taste APIs / improvement in palatability,

materials densification,

compactability and compressibility enhancement of the APIs,

drug release control,

reduction of dust, and

improvement in tablet physical properties

Wet granulation is a process in which a liquid binder is added to the powder mixture and

agitation is used to form granules.

1.2.1.1 Advantages

Improvement of cohesiveness and compressibility of powders; hence the tablet

compressibility is improved.

Drugs exhibiting a high dose and poor flowability and/or compressibility; their

flowability and cohesion for compression will be improved by wet granulation.

The uniformity and distribution of soluble, low dosage drugs and colour additives can be

obtained, especially if these materials are distributed in the granulation solution. Also it

prevents segregation of components of a homogeneous powder during processing and

transfer.

The dissolution rate of insoluble drugs can sometimes be improved by wet granulation.

http://en.wikipedia.org/wiki/Granulation



Dry GranulationWet GranulationDirect Compression

Mixing/ blending of API

and excipients

Tablet compression /

Capsules filling

Preparation of blinder

solution

Preparation of slugs/

compacts (by compression

or roll compaction)

Wet granulation process

using binder solution

Drying of wet granules

Screening of wet mass

Milling/sieving of dried

granules/ slugs

Dry mixing of sieved granules with final

mixing excipients (e.g., Lubricant,

disintegrant, filler, etc.)

Figure 1.1 Comparison of steps involved in the different processing techniques for

solid dosage form preparations.



1.2.1.2 Limitations

The main disadvantage of wet granulation is its cost because of the space, time and

equipment involved. For the following reasons, the process is labour intensive.

Long processing steps are involved and a relatively large space is needed for the

preparation area.

Different types of expensive equipment are required.

It is time consuming, especially for the granulation and drying steps.

The manufacturing yield is much lower when compared with direct compression

processing techniques because of the material losses in multi-step processes.

There is a greater possibility of cross-contamination, as there are many steps involved

compared to direct compression.

Drug release is slower, sometimes due to stronger binding.

Many process variables including mixing, granulation, drying, granule sizing and final

mixing are involved in the validation of the manufacturing process which is required to

insure the consistency of the process.

Additional testing (e.g, gas chromatography) is required for residual solvents when non-

aqueous granulation is performed.

1.2.2 Dry Granulation [12, 13]

Dry granulation is used to form granules without using a liquid solution or it refers to

the process of densification via roller compaction, followed by gravity

milling/screening to give the required particle size distribution. This process is used

when the product is sensitive to moisture and heat. Commonly, dry granulation

processes can be conducted using slugging tooling via tablet compression machinery

or by using other specialized machines such as a roller compactor.

1.2.2.1 Advantages

Overcomes poor physical properties of API (particle size, shape).

Improves the flowability, content uniformity, and compaction properties of powders.

Dry granulation equipment offers a wide range of pressure and roll types to attain proper

densification.

The process cycle is often reduced and equipment requirements are minimized; thus the

cost is reduced.



1.2.2.2 Limitations

Dry granulation often produces a higher percentage of fines or non-compacted products,

which can affect the quality or create yield problems in the tablet produced.

Requires drugs or excipients with cohesive properties.

Longer processing time when compared to direct compression process which may

compromise compactibility.

1.2.3 Direct compression [11, 14]

This method is used when a group of ingredients can be blended and compressed into

tablets without any of the ingredients having to be changed. Powders that can be

blended and compressed are commonly referred to as direct compression excipients.

1.2.3.1 Preparation methods of direct compression excipients

Direct compression excipients can be produced by different technelogies. The

advantages, limitations and main features of the methods are listed in Table 1.4.

Table 1.4 Methods used to prepare direct compression excipients.

Method Advantages and limitation Examples

Chemical

modification

- Relatively expensive

- Toxicological data required

- Time consuming

Ethyl cellulose, methylcellulose, and

sodium carboxymethyl cellulose from

cellulose, lactitol

Physical

modification

Relatively simple and economical Dextrates of compressible sugar,

sorbitol

Grinding and/or

sieving

Compressibility may alter because of changes

in particle properties such as surface area and

surface activation

Pharmatose® 150M, Pharmatose

®

100M, Pharmatose® 50M, Capsulac

®

60, PrismaLac® 40

Crystallization Import flowability to excipient but not

necessarily self-binding properties, require

stringent control on possible polymorphic

conversions and processing conditions

-lactose, dipac

Spray drying Spherical shape and uniform size gives spray-

dried materials good flowability- poor

reworkability

Spray dried lactose, Avicel PH, TRI-

CAFOS

S, Advantose 100 maltose

powder. FlowLac® 100, Pharmatose

®

DCL 11

Granulation/

agglomeration

Transformation of small particle, cohesive,

poorly flowable powders into flowable and

directly compressible powders

Granulated Lactitol, Tablettose® 70,

Tablettose® 80

Dehydration Increased binding properties by thermal and

chemical dehydration Anhydrous -lactose

http://www.ualberta.ca/~csps/JPPS8(1)/P.Jogani/excipients.htm#Table 3



1.2.3.2 Advantages and limitations of direct compression processes

In direct compression the manufacturing cycle is much shorter and the product yield

is much higher than wet or dry granulation techniques. Less manufacturing steps and

machines are involved in direct compression, resulting in a reduction in the

processing costs. Regarding the product quality, the most significant advantage is that

processing is performed in the absence of moisture and heat. The critical issue in

direct compression formulations is the choice of excipients involved (e.g. the

compressibility and flowability of the fillers/binders). The particle size distribution,

strength, compactability and the physical properties of the API also play an important

role in using this process. The critical issues, advantages and limitations which may

occur in direct compression processes are outlined in Table 1.5.

Table 1.5 Critical issues, advantages and limitations of direct compression.

Critical Issues Advantages Limitations

Flowability Cost effective production Segregation, problems in the

content uniformity of the API

Compressibility and

compactibility

- Better stability of API

- Retains compactibility of materials

Tablet weight variation due to

poor flow properties

Dilution potential Faster dissolution rate Low dilution potential

Reworkability (reprocessing) Less wear and tear of punches Re-workability

Stability Simple process validation High content of poorly

compressible APIs

Controlled particle size Lower microbial contamination Lubricant sensitivity

Direct compression excipients, especially fillers and binders, are mostly common

excipients modified using special procedures to improve their flow properties and

compressibility. The physical and chemical properties of this special type of excipient

are of significant importance when they are manufactured or involved in formulation

design. Many factors are involved in the selection of a suitable, direct compression

excipient which is to be used in tablet formulation including powder characteristics,

solubility, stability, compatibility, flowability, compressibility and cost. Examples of

some commercially available direct compression excipients are listed in Table 1.6 [9,

15].



Table 1.6 Examples of commercially available direct compression excipients.

Excipient Brand Name (Manufacturer, country)

Lactose Tablettose (Meggle, Germany), pharmatose (DMV, the Netherland), fast-flo

lactose (Foremost)

Microcrystalline cellulose/cellulose Avicel PH (FMC, USA), Emcocel (Edward mendell, USA, Vivacel (JRS, USA)

Mannitol Mannogem 2080 (SPI Polyols, France), Sorbidex P (Cerestar, USA)

Starch Starch 1500 (Colorcon, USA Spress B820 (GPC, USA) Era Tab (Erawan,

Thialand), Purity (National starch, USA), pharm DC 93000 (Cerestar, USA)

Di-calcium phosphate Emcompress (JRS, GmbH), A-Tab and Di-Tab (Rhodia, USA)

Tri-calcium phosphate Tri-Tab (Rohodia, USA)

Sorbitol Neosorb 60 (Roquette, France) sorbogem (SPI polyols, France), sorbidex P

(Cerestar, USA)

Sucrose Di-pac (American sugar company, USA), NuTab (ingredient technology Inc.,

USA)

Dextrose Emdex (Edward mendell, USA)

Lactitol Finlac DC (Danisco, USA ), Lacty-TAB (Purac, USA)

Xylitol Xylitab (Danisco, USA)

Maltodextrin Maltrin (Grain Processing Corp, USA)

Powdered Cellulose/Cellulose Elcema (Allchem Pharma, UK)

Calcium sulphate Destab (Particle Dynamics, USA)

Calcium lactate penta-hydrate Puracal DC (Purac, USA)

Calcium lactate tri-hydrate Puracal TP (Purac, USA)

Aluminium hydroxide Barcroft (SPI Polyols, France)

1.3 Co-Processed Excipients [8, 16]

There are three possible procedures by which a new excipient can be developed:

new chemical entities as excipients,

new grades of already existing excipients, and

new combinations of existing excipients.

Additionally, regulatory expectations of safety and toxicity properties ensure that new

chemical entities being developed as excipients undergo various stages of scrutiny,

which is a lengthy and costly process. Furthermore, the excipient is required to

undergo a phase of generic development which shortens the market exclusivity

period. Accordingly, modification of the physicochemical properties of existing

excipients has been the most successful strategy to produce new functional excipients.



The introduction of high-speed tablet compression machines and the shift in tablet

manufacturing toward direct compression process have encouraged the search for new

excipients meeting special requirements. Tablet formulators have recognized that

single component excipients do not always provide the requisite performance to allow

certain active pharmaceutical ingredients to be formulated or manufactured

adequately. In response to these deficiencies, they have relied on increasing numbers

of combination excipients introduced by excipient manufacturers into the commercial

market (Table 1.7). Combination excipients fall into two broad categories.

1.3.1 Physical mixtures

Physical mixtures are simple admixtures of two or more excipients typically produced

by short duration low shear processing. They may be either liquids or solids and are

generally used for convenience rather than for facilitating the manufacturing process

or improving the resultant pharmaceutical product. Examples of such physical

mixtures include immediate release film coating powders for dispersion that reduce

the time required to prepare film coating suspensions and to minimize colour variation

of the final product. Such physical mixtures are not appropriate for consideration for

National Formulary (NF) monographs because the individual components are isolated

(distinct and intact) before mixing; i.e., the manufacturing process for each of the

individual components has been taken to completion, and consequently these

components can be adequately controlled before mixing.

1.3.2 Co-processed excipients

Co-processed excipients can be defined as a combination of two or more excipients

that possess performance advantages that cannot be achieved using a physical

admixture of the same combination of excipients. Co-processing of excipients was

introduced in the pharmaceutical industry in the late 1980s, by e.g. co-processing

MCC and calcium carbonate followed by “Cellactose” (Meggle, Germany) in 1990, a

co-processed combination of cellulose and lactose, and silicified microcrystalline

cellulose (SMCC) in 1996, a co-processed product of MCC and colloidal silicon

dioxide (CSD).



Table 1.7 Commercially marketed co-processed direct compression excipients.

CO-PROCESSED EXCIPIENTS TRADE NAME MANUFACTURER ADVANTAGES/FUNCTION

Lactose monohydrate (93%), Kollidon 30

(3.5%), and Kollidon CL (3.5%) Ludipress

BASF AG. Ldwigshafen,

Germany

Lower hygroscopicity, good flow ability, tablet hardness independent

of machine speed

Lactose monohydrate (96.5%) and

Kollidon 30 (3.5%) Ludipress LCE

BASF AG, Ludwigshafen,

Germany Lower hygroscopicity, higher tablets hardness

α-Lactose monohydrate (75%) and

cellulose powder (25%) Cellactose 80

Meggle GmbH &, Co. KG,

Germany Highly compressible, good mouth feel, better tabletting at low cost

α-Lactose monohydrate (75%) and MCC

(25%) MicroceLac 100

Meggle GmbH &, Co. KG,

Germany Capable of formulating high-dose small tablets with poor flowability

α-Lactose monohydrate(85%) and maize

starch (15%) starLacTM Roquette, Lestrem, France Good flow, optimized disintegration, excellent tablet hardness

Anhydrous β-lactose (95%) and lactitol

(5%) Pharmatose DCL-40

j. Rettenmaier & Sohne GmbH

& Co. KG, Germany High compatibility, superior flow properties, low lubricant sensitivity

Silicified microcrystalline cellulose

(SMCC) [microcrystalline cellulose

(MCC) 98% and colloidal silicon dioxide

(CSD) (2%)]

ProSolv HD 90, ProSolv SMCC 50, ProSolv SMCC 90

FMC Biopolymer, Newark,

Delaware, U.S.A.

High compatibility, high intrinsic flow, good blending properties,

reduced sensitivity to wet granulation, better tablet hardness

MCC and guar gum Avicel CE-15 FMC BioPolymer, Netwark,

Delaware, U.S.A.

Less grittiness, reduced tooth packing, minimal chalkiness, creamier

mouth feel, improved overall palatability

MCC and carboxymethylcllulose sodium Avicel RC-581, RC-591, CL-661 FMC BioPolymer, Netwark,

Delaware, U.S.A.

Viscosity regulator and modifier , thixotropic characteristics, heat and

freeze-thaw stable, long shelf-life stability, lengthy hydration times

eliminated, stable in the 4-11 pH range

MCC and calcium phosphate Celocal FMC BioPolymer, Netwark,

Delaware, U.S.A. Direct compression excipient

MCC (65%) and calcium carbonate (35%) Vitacel VE-650 FMC BioPolymer, Netwark,

Delaware, U.S.A. Direct compression, encapsulation

MCC and carrageenan LustreClear TM FMC BioPolymer, Netwark,

Delaware, U.S.A.

Efficient tablet-coating with short hydration time prior to coating and

fast drying time

Mannitol 85%, crospovidone 10%, sorbitol

5%, silicon dioxide <1%. Pharmaburst TM B2

SPI Pharma TM, Inc., New

Castel , U.S.A/

High compactibility, high loading in small diameter tablets, smooth

mouth feel, rapid disintegration Mannitol 84%, crospovidone 16%, silicon

dioxide <1% Pharmaburst TM C1

Fructose (95%) and starch (55) AdvantoseTM FS Fructose SPI Pharma TM, Inc., New

Castel , U.S.A/

Excellent flow, good compressibility, tablets hold shape well, but are

very chewable



Table 1.7. (continued)

CO-PROCESSED EXCIPIENTS TRADE NAME MANUFACTURER ADVANTAGES / FUNCTION

MCC, mannitol Avicel HFE102 FMC, USA High compatibility, superior flow properties, low lubricant sensitivity

Xylitol, carboxymethyl cellulose sodium XyliTab Danisco Sweeteners,

Finland Artificial sweeteners for medical purposes

Vinylacetate, vinylpyrollidone Plasdon S-630

(Copovidone) ISP, USA

Excellent tablet binder, matrix polymer

for solid dispersions and film former for topical applications

Sucrose (97%) and dextrin (3%) Di-Pac American Sugar Co, New

York, U.S.A. Direct compression excipient

Calcium carbonate, starch Barcroft CS 90

SPI Pharma, France

Directly compressible calcium carbonate

Aluminium hydroxide, magnesium hydroxide, sorbitol

and mannitol Barcroft AHMN

A free flowing, highly reactive, and directly compressible antacid

powder

Calcium carbonate (70%) and sorbitol (30%) Formaxx CaCO3 70 Merck KGaA, Darmstadt,

Germany.

High compressibility, excellent taste masking, free flow, superior

content uniformity, controlled particle size distribution

Calcium carbonate, acacia Carbofarma GA10 Resinas industrials,

S.A., Argentina Directly compressible calcium carbonate

Calcium carbonate, maltodextrin Carbofarma GM11

Polyhydric sugar alcohol (75%), proprietary silicate salt

(25%) PanExcea MC200G

Malinkrodt Baker/USA

High performance rapid disintegrating direct compression excipient for

oro-dissolving tablets formulation.

MCC (89%), hydroxypropylmethyl cellulose (HPMC) 2%

and crospovidone (9%) PanExcea MHC300G High performance excipient for immediate release formulation



Co-processing is typically performed using some form of specialized manufacturing

process such as high shear dispersion, granulation, spray drying, or melt extrusion. It

is the one of the most widely explored and commercially utilized method for the

preparation of direct compression excipients. Co-processing offers the following main

advantages.

Provides a single excipient with multiple functionalities.

Produces a product with added value related to the ratio of its functionality

against price.

Improved compressibility and flow properties. Better dilution potential can be

obtained where co-processed excipient possess a higher dilution potential than

a physical mixture of its constituent excipients (dilution potential is defined as

the amount of an active ingredient that can be satisfactorily compressed into

tablets along with the direct compression excipient at a minimum possible

weight).

Allows the development of superior excipients by keeping functionality and

removing undesirable properties, which helps in faster product development.

Improvement in organoleptic properties (e.g., a co-processed excipient of MCC

and guar gum, designed for providing chewable tablets with reduced grittiness

and tooth packing, minimal chalkiness, better mouth feel, and improved

overall palatability).

Provides more robust tablets at low compression force. Co-processing of

mannitol with sorbitol results in excipients with stronger binding capacity.

This permits the packaging of orally dissolving tablets (ODTs) in conventional

HDPE bottles, eliminating the need for specialized packaging where

significant cost reduction can be achieved.

Reduces product cost due to improved functionality and fewer test requirements

compared to individual excipients.

Provides intellectual benefits in terms of proprietary combinations, specific for

in-house use.

Co-processing is another way that new excipients are coming to market without

undergoing the rigorous safety testing of a completely new chemical entity.



Co-processed excipients development generally starts by designing the following

factors.

The selection of the excipients to be combined and their targeted proportion.

The selection of the preparation method to obtain an optimized product with the

desired physicochemical parameters.

Optimization of the preparation method to assure process reproducibility and

product quality and functionality.

An overview of the co-processing methodology is shown in Figure 1.2.

Figure 1.2 Co-processing methodology.



1.3.3 Role of Material Characteristics in Co-Processing [8, 17]

Material science plays a significant role in altering the physico-mechanical

characteristics of excipients, especially with regard to their compression and flow

properties. The solid materials can be classified according to their response towards

applied mechanical force into three categories (Table 1.8): elastic, plastic and brittle

(Figure 1.3.A).

Table 1.8 Material classification according to their response to applied mechanical force.

Material classification Description

Elastic Any change in shape is completely reversible, and the material returns to

its original shape upon release of applied stress.

Plastic Permanent change in the shape of a material due to applied stress, e.g.,

MCC, corn starch, and sodium chloride.

Brittle

Rapid propagation of a crack throughout the material on application of

stress, e.g., sucrose, mannitol, sodium citrate, lactose, and di-calcium

phosphate.

The predisposition of a material to deform in a particular manner depends on its

lattice structure; in particular whether weakly bonded lattice planes are inherently

present. In definitive terms, most of the materials cannot be classified distinctly into

individual categories. Pharmaceuticals exhibit all three characteristics, with one of

them being the predominant response, thus making it difficult to clearly demarcate the

property favorable for compressibility. Compression refers “to a reduction in the bulk

volume of materials as a result of displacement of the gaseous phase”. Stages

involved in the bulk reduction of powdered solids are shown in Figure 1.3.B. There

are four stages encountered during compression:

(I) initial repacking of particles,

(II) elastic deformation of the particles until the elastic limit (yield point) is

reached,

(III) plastic deformation and/or brittle fracture then predominate until all the

voids are virtually eliminated, and

(IV) compression of the solid crystal lattice then occurs.

At the onset of the compression process, when the powder is filled into the die cavity,

and prior to the entrance of the upper punch into the die cavity, the only forces that



exist between the particles are those that are related to the packing characteristics of

the particles, the density of the particles and the total mass of the material that is filled

into the die (Figure 1.3.B.I).

Figure 1.3 (A) Material classification on the basis of deformation behavior in the

presence of an applied mechanical force, (B) stages involved in compression (I-III)

and decompression.

Packing characteristics of a mass of dry powder are determined, in large part, by the

characteristics of the individual particles. When external mechanical forces are

applied to a powder mass, there is usually a reduction in volume due to closer packing

(A)

(B)



of the powder particles and, in most cases, this is the main mechanism of initial

volume reduction (Figure 1.3.B.II). However, as the load increases, rearrangement of

particles becomes more difficult and further compression leads to some type of

particle deformation (Figure 1.3.B.III). If on removal of the load (decompression), the

deformation is, to a large extent, reversible (behaves like rubber) then the deformation

is said to be “elastic”. All solids undergo elastic deformation, to some extent, when

subjected to external forces. In some groups of powdered solids, an elastic limit is

reached, and loads above this level result in deformation not immediately reversible

on the removal of the applied force. Bulk volume reduction, in such cases, results

from plastic deformation and/or viscous flow of particles, which are squeezed into the

remaining void spaces. This mechanism predominates in materials in which the shear

strength is less than the tensile or breaking strength. Plastic deformation is believed to

create the greatest number of clean surfaces. Because plastic deformation is a time

dependent process a higher rate of force application leads to the formation of less new

clean surfaces and thus results in weaker tablets. Furthermore, since tablet formation

is dependent on the formation of new clean surfaces, high concentrations or over

mixing of materials that form weak bonds result in weak tablets (e.g, over mixing the

granules with magnesium stearate may produce weak tablets due to the formation of

weak bonds and easily wet surfaces). Conversely, in materials in which the shear

strength is greater than the tensile strength, some particles may be preferentially

fractured, and the smaller fragments then help to fill up the adjacent air spaces. This is

most likely to occur with hard, brittle particles and is known as “brittle fracture”;

sucrose behaves in this manner. The ability of a material to deform in a particular

manner depends on the lattice structure; in particular whether weakly bonded lattice

planes are inherently present. Brittle fracture creates clean surfaces that are brought

into intimate contact by an applied load. Irrespective of the behavior of large particles,

small particles may deform plastically via a process known as “microsquashing”, and

the proportion of fine powders in a sample may therefore be significant.

Co-processing offers an interesting tool for altering these physico-mechanical

properties of excipients. It is generally conducted using plastic and brittle excipients.

In this regard cellactose is an appropriate example which involves co-processing of

75% lactose (a brittle material) with 25% cellulose (a plastic material). Use of this

particular combination prevents the storage of excessive elastic energy during



compression, resulting in a small amount of stress relaxation and a reduced tendency

for capping and lamination. However, examples at the other extreme also exist, e.g.,

silicified microcrystalline cellulose (SMCC) which contains a large amount of

microcrystalline cellulose (MCC) (a plastic material) and a small amount of colloidal

silicon dioxide (CSD) (a brittle material). These two cases exemplify the fact that co-

processing is generally performed by using a combination of materials possessing

plastic deformation and brittle fragmentation characteristics.

Particle properties have a direct influence on excipient functionalities such as the

potential for dilution, disintegration, and lubrication. Therefore, when developing a

new excipient particle design must be taken into consideration. The role of particle

engineering, by varying various particle properties, in achieving the desired excipient

functionalities is shown in Table 1.9.

Table 1.9 Particle properties influencing excipient functionality.

Particle property Affected excipient functionality

Particle size Flowability, content uniformity, compressibility,

disintegration, dissolution rate

Particle size

distribution

Segregation potential

Particle shape Flowability, content uniformity, compressibility

Particle porosity Compressibility, disintegration, dissolution rate

Surface roughness Flowability, segregation potential, dilution

potential, lubricant sensitivity

1.3.4 Characterization of Co-Processed Excipients [8, 14, 18]

Formulations are developed by characterizing particles, powders, and compacts of

API and excipients. Such characterization is associated with some predictive tools and

allows formulators to understand the important physical, chemical, and mechanical

properties of materials and thus design robust formulations at a relatively low cost and

to achieve acceptable exposure in clinical studies.

The improvement in performance due to co-processing is the driving force for the

introduction of excipients into the market. The absence of any chemical reaction

between individual ingredients in the co-processed excipient must initially be



analytically demonstrated and over the proposed storage period of the co-processed

excipient using different analytical techniques (e.g. X-ray powder diffraction

spectroscopy (XRPD), Fourier-transform infra-red (FTIR) spectroscopy, differential

scanning calorimetry (DSC), scanning electron microscope (SEM), etc.). The

performance and functionality of the developed co-processed excipient should be

evaluated using different testing procedures to prove the added value over the

individual components properties. Table 1.10 presents the important parameters

involved in the evaluation of co-processed and direct compression excipients.



Table 1.10 Parameters involved in the evaluation of co-processed and direct compression excipients.

Property Related parameters Comments

Tab

let

char

acte

rist

ics

Lubricant sensitivity

Lubricant, especially metal stearates, reduce the tensile strength (due to

reduction of inter-particle bonding) and/or make the API hydrophobic

and thereby prolong the disintegration time or decreases it on long,

intensive mixing. The material undergoing plastic deformation is more

susceptible to the negative effect of lubricant.

Re-workability (re-

processing)

This is the ability to reprocess a defective batch. Re-workability is

influenced by the deformability of the directly compressible adjuvant on

initial compression.

Tensile strength, friability,

and disintegration time

These are important parameters for the quality control of tablets. The

mechanical properties of a tablet are the consequence of consolidation

and expansion phenomenon. The increase in particle surface contact

promotes a greater propensity for increased bonding. Tablets should have

sufficient tensile strength to hold the API intact at the lowest

compression force. Simultaneously it should give low friability and

desired disintegration time.

Dilution potential and

loading capacity

High dilution potential is desirable to produce tablets with less weight.

Compressibility and flowability of the drug has a strong influence on it.

Others parameters such as moisture absorption or stability upon storage can be used to compare the performance of directly

compressible excipients.

Pow

der

Char

acte

rist

ics

(Flo

w-a

bil

ity) Angle of repose, Carr’s

index (Compressibility

index) and Hausner’s ratio

Carr’s index (C) is an indication of the compressibility of a powder. It

is calculated by the formula: C = 100 VT - VB / VT , where VB is the bulk

volume of a given mass of powder, and VT is the tapped volume of the

same mass of powder.

Hausner’s ratio (H) is an indication of powder flowability and it is

measured by the ratio: tapped density / bulk density.

Angle of repose (θ) is defined as the maximum angle possible between

the surface of a pile of powder and the horizontal plane.

(θ = tan-1

h/r ) where, h = height of the cone, r = radius of the cone base

According to US pharmacopeia 31, General chapter <1174 >, angle of

repose (25-30) indicates excellent flow, and 31-35 indicate good flow.

Carr’s index ≤10 indicates excellent flow whereas 11-15 indicates good

flow. Hausner’s ratio less than 1.0-1.11 indicates excellent flow, whereas

1.12–1.18 indicates good flow. Good flowability of powder is needed for

content uniformity and less weight variation in final tablets.

Bulk density/Tapped density

Bulk density is defined as the mass of a powder divided by the bulk

volume and has units of gm/cm 3.

Tapped density is the ratio of the mass of the powder to the volume

occupied by the powder after it has been tapped for a defined period of

time.

The bulk density of a powder mainly depends on particle size

distribution, particle shape and the tendency of particles to adhere

together. The bulk and tapped density values influence the ability of the

material to undergo compression and the final volume of the tablets.

Particle size distribution

- Mean particle size

- Percentage fines

The angle of repose and Hausner’s ratio are based on the ability of a

mass of powder to flow. The flowability of the direct compression

excipient is influenced by particle size and shape. Fine powder retards

the flow, whilst particles with uniform size and shape exhibit better flow

than irregular particles of the same size and shape.

http://en.wikipedia.org/wiki/Compressibility

http://en.wikipedia.org/wiki/Powder

http://en.wikipedia.org/wiki/Formula



Property Related parameters Comments

Pow

der

Char

acte

rist

ics

(Com

pre

ssib

ilit

y)

Heckle and Kawakita

equations

A direct compression excipient should exhibit an acceptable pressure-

volume profile (compressibility). Heckle and Kawakita equations are

most widely used to assess material compressibility. The slope, k, of the

Heckle plot gives a measure of the plasticity of a compressed material

and the reciprocal of k is known as the yield value (Py). The yield value

reflects the deformability of the material; soft, ductile powders have a

lower yield value, the agglomerates with low yield value can be

plastically deformed as a result of the rebinding of smaller primary

crystals. Low values of Py (steep slope) reflect low resistance to pressure,

good densification and ease of compression. A large slope value indicates

the onset of plastic deformation at relatively low pressure.

In

D1

1=kP+A (Heckel Equation)

where, D is the relative density of a powder compact at pressure P. The

constant k is a measure of the plasticity of a compressed material. The

constant A is related to the die filling and particle rearrangement before

deformation and bonding of the discrete particles.

The Kawakita equation is used to study powder compression using the

degree of volume reduction, C. The basis for the Kawakita equation for

powder compression is that particles subjected to a compressive load in a

confined space are viewed as a system in equilibrium at all stages of

compression, so that the product of the pressure term and the volume

term is a constant:

C = [V0 – V/V0] = [abP/1 + bP] (Kawakita Equation) where, C is degree of volume reduction, V0 is the initial volume; V is the

volume of powder column under the applied pressure P. The a value is

the material’s minimum porosity before compression while b relates to

plasticity of the material. The smaller a value for the granules indicates

good packing even without tapping. The large value of b indicates rapid

packing velocity of the powder or agglomerates. The reciprocal of b

defines the pressure required to reduce the powder bed by 50%. The

equation above can be rearranged in linear form as:

P/C = P/a + 1/ab

The expression of particle rearrangement could be affected

simultaneously by the two Kawakita parameters a and b. The

combination of these into a single value, i.e. the product of the Kawakita

parameters a and b, may hence be used as an indicator of the expression

of particle rearrangement during compression.

Functionality

Co-processed excipient can involve APIs using different processing

techniques including direct compression, wet or dry granulation to assess

the capability of the co-processed excipient to maintain and preserve its

superior properties and functionality.

Moisture Uptake

(Hygroscopicity)

Moisture uptake is an important characteristic of pharmaceutical

powders. Many pharmaceutical excipients can sorb atmospheric

moisture. Moisture has a significant impact on the physical stability,

chemical stability, flowability, and compactibility of powder excipients

and formulations (e.g., moisture-sensitive APIs formulation). Water

sorption and equilibrium moisture content depend upon the atmospheric

humidity, temperature, surface area, and exposure, as well as the

mechanism for moisture uptake [17].



1.4 Special Types of Excipients (Oro-Dissolving Tablets) [19, 20]

Oro-dissolving tablets (ODTs) are solid dosage forms containing medicinal

substances that disintegrate rapidly in the oral cavity and disperse in the saliva

without the need for water. In April 2007, the Food and Drug Administration (FDA)

issued draft guidance, Guidance for Industry: Orally Disintegrating Tablets [21]. The

definition considers ODTs to be solid oral preparations that disintegrate rapidly in the

oral cavity with an in vivo disintegration time of approximately 30 seconds or less,

when based upon the USP disintegration test method. Besides convenience of intake

the advantage of this dosage form is fast bioavailability of the active ingredient. The

mechanism behind the disintegration of ODTs is illustrated in Figure 1.4.

Figure 1.4 Mechanism of disintegration of ODTs.

Orally disintegrating tablets offer all the advantages of solid dosage forms and liquid

dosage forms together with special advantages, including the following.

ODTs are solid dosage forms which provide good stability, accurate dosing,

easy manufacturing, small packaging size and easy to handle by patients.

No risk of obstruction of dosage form, which is beneficial for traveling patients

who do not have access to water.

Easy to administer for pediatric, geriatric, mentally retarded and psychiatric

patients.



Rapid disintegration of tablet results in quick dissolution and rapid absorption

which provide rapid onset of action.

Medication as a "bitter pill" has changed because of acceptable mouth feel

properties produced by the use of flavors and sweeteners in ODTs.

Bioavailability of drugs that are absorbed from the mouth, pharynx, and

oesophagus is increased.

Pre-gastric absorption of drugs avoids hepatic metabolism, which reduces the

dose and increase the bioavailability.

Some challenges may be faced when developing and designing ODT solid dosage

forms including the following.

Achieving rapid disintegration of tablets.

Avoiding an increase in tablet size.

Obtaining sufficient mechanical strength for tablets.

Minimizing or avoiding residue in mouth.

Protecting tablets from moisture.

Good package design (necessary because of low tablet hardness).

Compatibility of API with taste masking technology.

Overcoming undesirable API properties.

Several technologies are commonly used by the manufacture of ODTs (Table 1.11).

These technologies differ in their methodologies and the ODTs produced vary in their

properties such as:

mechanical strength, wetting and disintegration time of tablets

taste and mouth feel

swallow-ability

drug dissolution in saliva

bioavailability

stability

The most common procedures are lyopholization (freeze drying) and direct

compression.



Table 1.11 Technologies used in ODT preparations.

Innovator/ Dosage form Technology Technology Basic Drug marker Marketed product/Indication

(CIMA Labs)

Direct compression tablet

Durasolv

Conventional direct compression tablets

containing API, filler, disintegrant,

flavourings, sweeteners, colorants and

lubricant.


containing API, filler, disintegrant,

flavourings, sweeteners, colorants and

lubricant.

Alamo Fazaclo (clozapine) / Antipsychotic

AstraZeneca Zomig-ZMT (zolmitriptan) / Migraine

Organon Remeron, SolTabs (mirtazapine)/ Depression

Schwarz Pharma

Fluxid (famotidine) / Duodenal ulcers

Orasolv


containing API, filler, disintegrant, flavourings,

sweeteners, colorants and lubricant.

NuLev (hyoscyamine sulfate) / Irritable bowel

Parcopa (carbidopa, levodopa) / Parkinson’s

disease

Wyeth Alvert (loratadine) /Allergy

(Ethypharm/BMS) Compressed tablet

Flash Tab A direct compression tablets consist of Eudragit-

microencapsulated API and effervescent couple

Bristol-Myers

Squibb

Excedrin, QuickTabs (acetaminophen, caffeine) /

Headache

(Yamanouchi) Compressed molded tablet

WOWTAB

(Without

water)

API is mixed with a low mouldability saccharide

(lactose, mannitol, maltose and maltilol) and

granulated with a high mouldability saccharide

and compressed into tablet

Pfizer Benadryl, Fastmelt (diphenhydramine citrate,

pseudoephedrine HCL / Allergy and sinus

(Cardinal Health)

Lyophilized (Freeze-

dried) wafer Zydis

A Zydis tablet is produced by lyophilizing

(freeze-drying) the API in a matrix usually

consisting of gelatin. Amorphous porous

structure is formed that can dissolve rapidly.

Freeze drying technique has demonstrated

improved absorption and increase in

bioavailability of APIs.

Eli Lilly Zyprexa, Zydis (olanzapine) / Schizophrenia

GlaxoSmithKline Zofran ODT (ondansetron) / Nausea and vomiting

Janssen Risperdal, M-Tab (risperidone)/Schizophrenia

Merck Maxalt-MLT (rizatriptan benzoate) / Migraine

Schering-Plough Claritin, Resitags (loratadine) / Allergy

Clarinex. Reditabs (desloratadine) / Allergy

(Biovail)

Floss-based tablet

technology Flash Dose

A sugar-based tablet matrix prpared in a

procedure similar to that used in the preparation

of cotton candy usind high temperature called

‘Floss’ is used to mask the bitter taste of API.

Reckitt Benckiser

Healthcare (UK)

Ltd

Nurofen meltlet/ NSAIDs



However, the number of fillers/binders that can be used for ODT formulations is

limited because these bulk excipients have to fulfil special requirements, such as

being soluble in water, having a pleasant sweet taste and mouth feel, as well as being

rapidly dispersible.

Direct compression ODT formulations usually contain the API, diluents/fillers,

disintegrants, lubricants, flavourings, sweeteners and colorants. The most commonly

used bulk excipients for the development of this kind of formulations are sugar based

excipients such as dextrose, fructose, isomalt, lactilol, maltilol, maltose, mannitol,

sorbitol, starch hydrolysate, polydextrose and xylitol, which display high aqueous

solubility and sweetness in addition to other favourable characteristics which improve

the performance and impart taste masking property of ODTs [22].

No single excipient can fulfil the requirements of all ODT formulations. A popular

way to enhance disintegration properties is the addition of a super-disintegrant, such

as croscarmelose sodium, sodium starch glycollate and crospovidone. Table 1.12

shows the most commonly used excipients/fillers for the preparation of ODTs.

Table 1.12 Commonly used excipients in ODT preparations.

Excipient Manufacturer Manufacturer Website

PanExcea MC200G Mallinckrodt Baker / USA http://www.mallbaker.com/panexcea/

Isomalt galenIQ-720 BENEO-Palatinit GmbH

(Germany)

http://www.beneo-

palatinit.com/en/Pharma_Excipients/galenIQ/galenIQ_Grades/

Isomalt galenIQ- 721

Ludiflash BASF / Switzerland http://www.pharma-ingredients.basf.com/Ludiflash/Home.aspx

Pharmaburst TM

SPI / FRANCE http://www.spipharma.com/default.asp?contentID=588

Pharmafreeze™

Mannitol (Mannogem)

Lactose Spry Dried (Fast-

Flu) Foremost / USA

http://www.foremostfarms.com/Commercial/Dairy-

Ingredients/Pharmaceutical-Grade-Lactose.php

http://www.mallbaker.com/panexcea/

http://www.beneo-palatinit.com/en/Pharma_Excipients/galenIQ/galenIQ_Grades/

http://www.beneo-palatinit.com/en/Pharma_Excipients/galenIQ/galenIQ_Grades/

http://www.spipharma.com/default.asp?contentID=588

http://www.foremostfarms.com/Commercial/Dairy-Ingredients/Pharmaceutical-Grade-Lactose.php

http://www.foremostfarms.com/Commercial/Dairy-Ingredients/Pharmaceutical-Grade-Lactose.php



1.5 Chitin: A Solid Dosage Form Excipient [23]

Lack of the amine group “NH2” makes chitin almost chemically inactive. In addition,

the availability of chitin as the second most naturally abundant material, after

cellulose, allows its use as an excipient in processing solid drug dosage forms. This

facilitates its use with other common excipients, namely microcrystalline cellulose

(MCC), lactose, starch, and calcium hydrogen phosphate. Consequently, chitin is a

natural hydrophilic polymer wherein chemical modification and co-processing can be

carried out to prepare multi-functional excipients.

1.5.1 Chemical names and structural formula of chitin (CAS No.: 8931 -61-4)

“Chitin” and “chiton” (a marine animal) both derive from the same Greek word

meaning “tunic”, referring to the protective shell. Chitin is a white, hard, inelastic,

nitrogenous polysaccharide found in the outer skeletons of crabs and lobsters as well

as in the internal structures of other invertebrates. Chitin (C8H31NO5)n is, β-(1,4)-2-

acetamido-2-deoxy-D-glucopyranose, poly-N-acetyl-D-glucosamine [poly (D-

GlcNAc)], β-1, 4-poly-N-acetyl-D-glucosamine, poly-(β1-4)-N-acetyl-glucosamine,

poly-(acetyl amino glucose), β- (1,4)-2-acetamido-2-deoxy-D-glucose, 2-acetamido-

2-deoxy-D-glucose, β-(1,4)-2-amino-2-deoxy-D-glucose, poly-(N-acetyl-1,4--D

glucopyranosamine), fully acetylated chitosan. Chitin has a monomer molecular

weight of 203.19 and average molecular weight ranging from 1.0 to 2.5 million Da.

The variation in the molecular weight is a function of the extent of

N-acetylation. The chemical structure of the monomeric unit of chitin is shown in

Figure 1.5. The elemental composition of fully acetylated chitin is: carbon: 47.29%,

hydrogen: 6.45%, nitrogen: 6.89% and oxygen: 39.37%.



Figure 1.5 Chemical structure of chitin showing its monomer: N-acetyl-D-

glucosamine [24].

1.5.2 Preparation of chitin

Crude chitin is isolated from the outer skeletons of crustaceans, molluscs or

invertebrate animals, insects and certain fungi. Commercially, crab and shrimp shells

are the major sources of chitin. Crustacean shells consist of 30-40% protein, 30-50%

calcium carbonate and 20-30% chitin, but also contain pigments of a lipidic nature

such as carotenoids. These components have to be quantitatively removed to obtain

pure chitin necessary for biological applications. Several published methods for the

extraction of chitin from crustacean shells in addition to enzymatic preparation are

summarized in Table 1.13.



Table 1.13 Methods for the preparation of chitin [25-28].

Method Procedure

Method 1

Crude chitin is washed with water, dried at room temperature and cut into small pieces, then treated

with acid (HCl, HNO3, H2SO4, CH3COOH, or HCOOH) (demineralization), followed by alkali using

NaOH at 105-110oC (deproteinization). The decolouration is performed by refluxing in ethanol or by

using oxidizing or bleaching agents (e.g. KMnO4, NaOCl and H2SO4).

Method 2

Crude chitin is washed with water, dried at room temperature and cut into small pieces, then soaked

for 3 days in 10% NaOH solution (freshly prepared and degassed every day at room temperature). The

obtained solid is then treated with 95% ethanol to clean the pigment products. The white protein free-

residue is then suspended in 37% HCl at 20°C for 4 hours. The solid is filtered and washed with water,

ethanol and ether.

Method 3

The shells are partially digested with an organic acid, followed by 2N HCl for 5 hours at room

temperature. The decalcified shells are shaken for 18 hours with 90% formic acid at room temperature

and then filtered. The solid is washed with water and treated for 2.5 hours with 10% NaOH solution on

a steam bath. The suspension is then filtered, washed with water, ethanol and ether.

Method 4

Decalcification with EDTA at pH 10 at room temperature for 2 or 3 weeks. Large cuticle fragments of

the crab Cancer parugus are reacted slowly (2 or 3 weeks) with EDTA at pH 9.0. The solid is then

further treated with EDTA at pH 3, extracted with ethanol for pigment removal and with ether for the

removal of lipids. The protein is removed with formic acid (98-100%) followed by treatment with hot

alkali.

Method 5

Decalcification with EDTA at pH 10 at room temperature, followed by digestion with a proteolytic

enzyme such as tuna proteinase at pH 8.6 and 37.5ºC, or papain at pH 5.5-6.0 and 37.5ºC or a bacterial

proteinase at pH 7.0 and 60ºC for over 60 hours. The remaining protein (~5%) is removed by

treatment with sodium dodecylbenzensulfonate or dimethylformamide.

Method 6

Decalcification is carried out by a simple treatment with 1.4N HCl at room temperature in a plastic or

wooden container. After completion of the decalcification treatment, proteins are removed using

papain, pepsin or trypsin. This method is simple and suitable for the mass production of chitin with

little deacetylation.

Method 7 The shell wastes are treated with hot 1% Na2CO3 solution followed by dilute HCl (1-5%) at room

temperature, and then 0.4% Na2CO3 solution

Method 8 Hydrolysis of protein present in the shell followed by digestion of CaCO3. The shells are treated with

hot 5% NaOH, followed by cold NaOCl and then with warm 5% HCl.

Method 9

Trehalose is hydrolyzed with the enzyme trehalase, followed by phosphorylation with ATP/enzyme

hexokinase to form glucose-6-phosphate, which is transformed to fructose-6-phosphate in the presence

of the enzyme glucose phosphate isomerase. Amination occurs in the presence of glutamine amino-

transferase and the amino acid glutamine to form -D-glucosamine-6-phosphate. Acetylation by

acetyl-CoA in the presence of the enzyme glucosamine-6- phosphate-N-acetyl transferase causes the

formation of N-acetylglucosamine-6-phosphate. The latter rearranges via the enzyme

phosphoacetylglucosamine mutase to form N-acetylglucosamine-1-phosphate, which is converted to

uridinediphosphate-N-acetyl glucosamine (UDP-N-acetylglucosamine) via the enzyme

uridinediphosphate-N-acetylglucosamine pyrophosporylase and UTP. The final product, chitin, is

produced via the enzyme chitin synthesase by the loss of UDP (Figure 1.6).



Figure 1.6 Biosynthesis of chitin [26].

1.5.3 Deacetylation of chitin (chitosan preparation)

The most important derivative of chitin is chitosan obtained by partial deacetylation

of chitin in the solid state under alkaline conditions or by enzymatic hydrolysis in the



presence of a chitin deacetylase. The ratio of 2-acetamido-2-deoxy-D-glucopyranose

to 2-amino-2-deoxy-D-glucopyranose moieties determines the identity of the product

i.e. chitin or chitosan. Published methods used for the production of chitosan from

chitin are summarized in Table 1.14.

Table 1.14 Methods used for the deacetylation of chitin to form chitosan [26, 27, 29,

30].

Method Procedure

Method 1 40% NaOH solution is added to chitin and refluxed under nitrogen at

115°C for 6 hours. The cooled mixture is then filtered and washed

with water until the washings are neutral to phenolphthalein. The

crude chitosan is purified as follows. It is dispersed in 10% acetic

acid and then centrifuged for 24 hours, to obtain a clear supernatant

liquid. The latter is treated drop-wise with 40% NaOH solution and

the white flocculent precipitate formed at pH 7. The precipitate is

then recovered by centrifugation, washed repeatedly with water,

ethanol and ether and the solid collected and air-dried (Figure 1-7).

Method 2 Fusion with solid KOH at very high temperature in a nickel crucible

under nitrogen atmosphere. The melt is poured carefully into ethanol

and the precipitate washed with water to neutrality.

Method 3 Heating in 40% NaOH solution at 115 ºC for 6 h under nitrogen.

After cooling, the mixture is filtered and washed with water until

neutral. This method does not include a purification step.

Method 4 Kneading with NaOH and liquid paraffin in a 1:1:10 ratio, and stirred

for 2 h at 120°C. The mixture is poured into cold water, filtered and

thoroughly washed with water.

Method 5 Steam heating with a solution containing 50% KOH, 25% EtOH

(96%) and 25% mono-ethylene glycol. The temperature of the system

is 120°C. The obtained chitosan is filtered, washed with water until

neutral, and then dried at moderate temperatures.

Method 6 Recovery of shell proteins, sodium acetate and calcium carbonate in

addition to chitosan as commercial pure products. The extraction

procedure includes different reaction and crystallization steps.

Method 7 The fungal order mucorales contains chitosan as a cell wall

component. Absidia coerula a member of this class is readily

cultured on nutrients (e.g. glucose or molasses) and the cell wall

material recovered by simple chemical procedures.



Figure 1.7 Scheme for the deacetylation of chitin [29].

1.5.4 Hydrolysis products of chitin (oligomers)

Chitin is hydrolyzed to form smaller oligosacharides by different methods including

acetolysis using acetic anhydride/H2SO4, hydrolysis with HCl/sonolysis under

ultrasound irradiation or fluorohydrolysis using anhydrous HF (Figure 1.8).

Enzymatic hydrolysis is a useful method for the preparation of monomers from chitin

and chitosan because the yield of monomers is greater by enzymatic hydrolysis than

by acid hydrolysis. The enzyme chitin deacetylase hydrolyzes the acetamido group in

the N-acetylglucosamine units of chitin and chitosan, thus generating glucosamine



units and acetic acid (Figure 1.9).

Figure 1.8 Mechanisms for the acid hydrolysis of chitin [31].

Figure 1.9 Enzymatic hydrolysis of chitin and chitosan into their monomers [31].



1.5.5 Other derivatives

Carboxymethyl chitin (CM-chitin), as a water-soluble anionic polymer, is the second

most studied derivative of chitin after chitosan. The carboxymethylation of chitin is

undertaken in a similar manner to that of cellulose. Chitin is treated with

monochloracetic acid in the presence of concentrated NaOH. The same cellulose

derivatization procedure can be used to prepare hydroxypropylchitin, which is a

water-soluble derivative used for artificial lachrymal drops. Fluorinated chitin, N- and

O-sulfated chitin, (diethylamino) ethylchitin, phosphoryl chitin, mercaptochitin and

chitin carbamates have also been reported and described in the literature. Similar

chemical modifications (e.g. etherification and esterification), as for cellulose, can be

performed for chitin. Chitin can be used in blends with natural or synthetic polymers;

it can be cross-linked by the reagents used for cellulose (e.g, epichlorhydrin and

glutaraldehyde) or grafted in the presence of ceric salt or after selective modification.

Another chitin derivative dibutyrylchitin (DBCH) is prepared from krill chitin by

esterification with butyric anhydride in the presence of perchloric acid. DBCH can be

used in fibre spinning. DBCH fibres have been manufactured from a polymer solution

in ethyl alcohol by extrusion.

1.5.6 Physical characteristics of chitin

1.5.6.1 Solubility

Table 1.15 Solubility of -chitin in different solvents and solvent mixtures at room

temperature [32-34]. Solvent/Solvent mixture Solubility

Water i

Dilute acids i

Dilute and concentrated alkalies i

Alcohol i

Organic solvents i

Concentrated HCl, H2SO4 or H3PO4, anhydrous HCOOH s (with depolymerization)

N,N-dimethylacetamide (DMAc)/5% LiCl s

Dinitrogen tetroxide/N,N-dimethylformamide (DMF) s

Fluoroisopropanol/hexafluoroacetone s

N,N-dimethylacetamide/N-methyl-2-pyrrolidone/LiCl s

N-methyl-2-pyrrolidone/5% LiCl s

i and s represent insoluble and soluble, respectively



The dissolution mechanism of -chitin in DMAc/5% LiCl (Table 1.15) can be

attributed to the formation of a weak complex between Li ions and the carbonyl

oxygens of the DMAc, which solvates the polyelectrolyte formed between the Cl

ions and labile proton groups (OH and NHCOCH3) of the chitin chain, disrupting the

extensive intra- and inter-molecular hydrogen bonds of the crystalline sheet structure

of -chitin.

Table 1.16 shows the effect of different solvent mixtures containing methanol, ethanol

and anhydrous and hydrate forms of calcium and magnesium salts.

Table 1.16 Solubility of -chitin in various calcium and magnesium salt-alcohol

solutions [32-34].

Solvent System Solubility*

Saturated anhydrous CaCl2-methanol p.s.

Saturated CaCl2.2H2O-methanol s

Saturated CaCl2.2H2O-ethanol p.s.

Saturated MgCl2.6H2O-methanol i

100%(w/v) Ca(NO3)2.4H2O-methanol i

100%(w/v) Mg(NO3)2.6H2O-methanol i

200%(w/v) Ca(SCN)2.4H2O-methanol p.s

*0.5g chitin was stirred in 50 mL of each solution at room temperature; s, p.s. and i represent soluble,

partially soluble and insoluble, respectively.

By comparing the solubility of - and β-chitins (although the later exists in a

crystalline hydrated structure, which is much looser than that of the α-chitin), β-chitin

shows lower solubility due to the penetration of water between the chains of the

lattice. Based upon data for chitin-solvent interactions and solubility mechanisms,

β-chitin starts gelling at a lower concentration than α-chitin. Table 1.17 shows the

solubility of chitin and structurally related compounds in a saturated CaCl2.2H2O-

methanol solvent system.



Table 1.17 The solubility of -/-chitins and structurally related compounds in a

saturated CaCl2.2H2O-methanol solvent system [32-34].

Material Solution (g/100 mL) Solubility*

α-Chitin 2.00 s

β-Chitin 1.25 t

Chitosan 5.00 i

Bacterial cellulose 0.15 g

O-Acetylated chitin 1.25 t

Nylon-6 5.00 s

*s, t, g, and i represent soluble, turbid or gelation, gelation and insoluble, respectively.

1.5.6.2 Chitin Morphology

The morphology of -chitin was determined using a Quanta-200 3D scanning

electron microscope (SEM) operated at an accelerating voltage of 1200 V. The

sample (0.5 mg) was mounted onto a 5×5 mm silicon wafer affixed via graphite tape

to an aluminium stub. The powder was then sputter-coated for 105 s at a beam current

of 20 mA/dm3 with a 100 Å layer of gold/palladium alloy. The SEM images in

Figure 1.10 show the highly porous structure of -chitin in addition to the high

particulate surface area.

A

B

Figure 1.10 SEM images of -chitin, at magnifications of (A) x160 and (B) x1600 [35].



1.5.6.3 Chitin polymorphs and their sources

Chitin is isolated from the exoskeletons of crustaceans (e.g, crabs, lobsters, crayfish,

shrimp, krill, barnacles), molluscs or invertebrate animals (e.g, squid, octopus,

cuttlefish, nautilus, chitons, clams, oysters, scallops, geoducks, mussels, fossils,

snails), insects (e.g. ants, scorpions, cockroaches, beetles, spiders, brachiopods) and

certain fungi. Commercially, crab and shrimp shells are the major sources of α-chitin

whereas squid is the source of β-chitin. There are three polymorphic forms of chitin:

α, β and γ. They differ in the arrangement of chains in the crystalline phase. The most

abundant and stable form is α-chitin, which displays orthorhombic crystals. The

crystallographic parameters for α- and β-chitin are shown in Table 1.18. The

neighboring sheets in - and -chitin are connected by hydrogen bonds via C=O and

N-H groups. In addition, each chain has intra-molecular hydrogen bonds between the

neighboring sugar rings (C=O and OH groups on C-6 and a second hydrogen bond

between the OH- group on C-3 and the ring oxygen) (Figure 1.11). The differences

among chitin polymorphs are due to the arrangement of the chains in the crystalline

regions. α-Chitin has a structure of anti-parallel chains, β-chitin has intra-sheet

hydrogen-bonding resulting in parallel chains and γ-chitin, being a combination of

α- and β-chitin, has both parallel and anti-parallel structures. Because of these

differences each chitin polymorph differs in specific properties. The poor solubility of

chitin is a result of the close packing of chains and its strong inter- and intra-

molecular bonds between the hydroxyl and acetamide groups. On the other hand,

β-chitin lacks these inter-chain hydrogen bonds; therefore it swells readily in water

and it is more prone to N-deacetylation than α-chitin.

Table 1.18 Crystallographic parameters for α-and β-chitin [36, 37].

Compound a (nm) b (nm) c (nm) γ() Space group

α-Chitin 0.474 1.886 1.032 90.0 P212121

β-Chitin 0.485 0.926 1.038 97.5 P21

http://en.wikipedia.org/wiki/Crab

http://en.wikipedia.org/wiki/Lobster

http://en.wikipedia.org/wiki/Crayfish

http://en.wikipedia.org/wiki/Shrimp

http://en.wikipedia.org/wiki/Krill

http://en.wikipedia.org/wiki/Barnacle

http://en.wikipedia.org/wiki/Squid

http://en.wikipedia.org/wiki/Octopus

http://en.wikipedia.org/wiki/Cuttlefish

http://en.wikipedia.org/wiki/Nautilus

http://en.wikipedia.org/wiki/Clam

http://en.wikipedia.org/wiki/Oyster

http://en.wikipedia.org/wiki/Scallop

http://en.wikipedia.org/wiki/Geoduck

http://en.wikipedia.org/wiki/Mussel



A

B

Figure 1.11 Modes of hydrogen bonding in (A) α-chitin: (a) intra-chain C(3)

OH···OC(5) bond; (b) intra-chain C(61)OH···O=C(71) bond; (c) inter-chain

C(61)O···HOC(62) bond; (d) inter-chain C(21)NH···O=C(73) and (B) -chitin:

(a) intra-chain C(3)OH···OC(5) bond; (b) inter-chain C(21)NH···O=C(73) bond

and C(6’1)OH···O=C(73) bond (ac plane projection); (c) inter-chain

C(21)NH···O=C(73) bond (ab plane projection) [36,37].

The seafood industry produces in excess of 3.5 million tonnes of solid waste each

year and with this figure rising, there is a subsequent waste disposal issue. Chitin is

mainly used as a raw material to produce chitin-derived products such as chitosans,

chitin/chitosan derivatives, oligosaccharides and glucosamine. An increasing number

of useful products derived from chitin continue to attract commercial development.

The large number of patents filed involving chitin-derived products reflects the

commercial expectations for these products. An estimated 75 % of chitin produced is

used to manufacture products for the nutraceutical market. Currently the major



driving force in the market is the increasing sales of glucosamine as a dietary

supplement. Approximately 65% of the chitin produced is converted into

glucosamine, nearly 25% is converted into chitosans, about 9% is used to produce

oligosaccharides and approximately 1% is used in the production of

N-acetylglucosamine. Table 1.19 shows the estimated global price of high purity

chitin, mannitol and different pharmaceutical grades of microcrystalline cellulose and

microcrystalline cellulose related products.

Table 1.19 Estimated global market prices of some pharmaceutical excipients [35].

Item Pharmaceutical Application Price* in USD/Kg

Chitin (high purity powder

grade)

Tablet/ capsule filler and

disintegrant 8-15

D-Mannitol (Crystalline) Tablet/ capsule filler 5-15

Microcrystalline Cellulose PH

200

Direct compression excipient

for tablet/ capsule formulation 6-10

Silicified Microcrystalline

Cellulose



AVICEL HFE 102 NF

(Mannitolized Microcrystalline

Cellulose)



* The price range is dependent on the quantity supplied, grade and supplier.

1.5.6.4 Chitin stability

Chitin is a stable compound, incompatible with oxidizing agents. In the solid state

under alkaline condition (e.g, NaOH, KOH, heat at about 120oC) or by enzymatic

hydrolysis in the presence of a chitin deacetylase, it hydrolyses to form the

deacetylated degradation product chitosan. It was found that the presence of urea in

basic media and at low temperature (-20oC) had little effect on chitin structure and

that urea is of benefit to the stability of chitin solution. Under acidic conditions

including acetolysis with acetic anhydride/H2SO4, hydrolysis with HCl/sonolyses

under ultrasound irradiation and fluorohydrolysis with anhydrous HF or by using the

enzyme chitin deacetylase, it forms smaller oligosaccharides. The effect of hydrogen

peroxide on the stability of chitin by microwave radiation was investigated, it was

suspended in water, and 30% hydrogen peroxide was added in quantities to achieve

H2O2 concentrations of 1%, 5%, 9% and then subjected to 600 W microwave



radiation for 10 to 30 min. The results indicated that chitin degradation with hydrogen

peroxide in a microwave field caused significant changes in the molecular weight and

the chemical structure of the polymer in a short period (up to 30 min). The limiting

viscosity numbers of the degradation products were from 15 to 83% lower than those

of the initial chitin.

1.5.6.5 Biodegradability and toxicology

Chitin is a biodegradable material and undergoes biodegradation by enzymes such as

lysozyme and chitinase. In-vivo studies show that lysozyme plays an important role in

the degradation of chitin to produce mostly soluble oligomers such as

N-acetylglucosamine upon hydrolysis. Chitin is not believed to present a significant

health risk. Also no risk to humans is expected when products containing chitin are

used according to label directions. Chitin is structurally closely related to the active

ingredient chitosan (poly-D-glucosamine), which shows no toxicity in mammals, and

is approved by the FDA as a food additive. The LD50 for the intravenous

administration of chitin is 50 mg/Kg in rats.

1.5.6.6 Chitin/ chitin derivatives applications

Chitin and its derivatives have been used in different applications including the food,

medical, pharmaceutical, agriculture and biotechnology industries. Table 1.20

illustrates some of these applications.



Table 1.20 Examples of applications of chitin and its derivatives [34, 38].

Fields Chitin and Chitosan Chitin and chitosan oligomers

Food Antimicrobial agent

preservative agent

Edible film

Antimicrobial agent

preservative agent

Pharmaceutical Protective effect on bacterial infection

Antitumor agents

Immunopotentiating agent

Carrier for drug delivery system

Protective effect on bacterial infection

Antitumor agents

Immunopotentiating agent

Medical Accelerator for wound healing

Artificial skin

Fiber for absorbable sutures

Nutritional Dietary fiber

Hypocholesterolemic agent

Antihypertensive agent

Hypocholesterolemic agent

Calcium absorption accelerator in vitro

Biotechnological Carrier for immobilized enzymes and cells

Porous bead for bioreactors

Resin for chromatography

Membrane material

Agricultural Seed coating preparation

Activator of plant cells

Activator of plant cells

Others Coagulant for wastewater treatment processing

plants

Removal of heavy metal from wastewater

Cosmetics material

1.5.6.7 Chitin in the pharmaceutical industry

Because chitin is a non-toxic material biodegradable material, it is attractive for use in

a wide variety of applications.

1.5.6.8 Chitin as a tablet/capsule disintegrant

Chitin is well known as a disintegrant in pharmaceutical solid dosage formulations in

tablets to facilitate their break up or disintegration after oral administration. Chitin, as

a disintegrant, can be used at the 2 – 20% (w/w) level.

1.5.6.9 Chitin as a tablet diluent and disintegrant

A study was undertaken of directly compressed tablet matrices containing chitin or

chitosan in addition to lactose, microcrystalline cellulose (MCC) or starch

formulation. Using lactose/chitin, lactose/chitosan, and lactose/MCC tablet hardness

increases with the addition of chitin, chitosan and MCC as shown in Figure 1.12.A.

Comparing the hardness of starch/MCC tablets with that of starch/chitin, there was no



statistical difference at 10 and 30% (w/w) addition. The hardness of the tablets

containing chitin, chitosan and MCC is increased by increasing the compression force

(Figure 1.12.B). This study also shows that the hardness of chitin tablets is greater

than that of chitosan due to the structural rigidity of chitin, attributed to the

acetylamino groups. Results suggest that chitin and chitosan can be used as direct

compression diluents. Rapid disintegration time was obtained for tablets produced

from lactose/chitin, lactose/chitosan, lactose/MCC, potato starch/chitosan and potato

starch/ MCC below a certain concentration level of excipient (chitin, chitosan and

MCC), as shown in Figure 1.12.C.

A

Compression pressure (kg/cm2)

Hard

ne

ss

(K

g) ’

Compression pressure (kg/cm2)

Hard

ne

ss

(K

g)

B

Excipient concentration (%w/w)

Ha

rd

ne

ss

(K

g)

300 mg Lactose tablets 200 mg Potato starch tablets



C

Excipient concentration (%w/w)

Dis

inte

gra

tio

n t

ime

(m

in)

300 mg Lactose tablets 200 mg Potato starch tablets

Figure 1.12 A) Relationship between tablet hardness and applied compression

pressure, B) relationship between the tablet hardness and concentration of used

excipient and C) relationship between tablet disintegration time and concentration of

excipient (x: disintegration was not completed within 60 min) [39,40].

1.5.6.10 Directly compressed tablets containing chitin or chitosan in addition to

mannitol

Mannitol is not a compressible material. The addition of chitin, chitosan and MCC

improves the compressibility of mannitol. The measured hardness for the tablets

composed of mannitol/chitin, mannitol/chitosan and mannitol/MCC increased with

increase in the concentration of chitin, chitosan or MCC (Figure 1.13). Chitin,

chitosan and MCC should be added at a level >20% w/w in order to improve the

compressibility of mannitol tablets. The relationship between the disintegration time

of tablets and the concentration of chitin chitosan or MCC excipients added to

mannitol were investigated. Results showed that all tablets obtained disintegrate

within 1 minute except for those containing 80% w/w chitosan [23].



Compression pressure (Kg/cm2))

Hard

ne

ss

(K

g)

Figure 1.13 The relationship between the tablet hardness and excipient concentration [40].

The compactibility of chitin and chitosan were evaluated by investigating the

relationship between applied compression pressure and obtained tablet crushing

strength (Figure 1.14). Chitin and chitosan exhibited almost identical compression

pressure-crushing strength profiles, being clearly more compressible than DBCP and

PGS. MCC showed the highest tablet crushing strength values (highest slope of the

curve). Table 1.21, shows the compression and friction properties (tensile strength,

net work, compactibility and R-value) of the chitin and chitosan in comparison with

the commercially available reference excipients at an applied compression pressure of

94 Mpa. The tensile strength and compactibility values for microcrystalline cellulose

(MCC) were the highest among the others, while chitin and chitosan presented similar

results of these parameters, and dibasic calcium phosphate (DBCP) the lowest values.

The excipients exhibited the same order with the present parameters as was found

with the compression profiles. MCC, chitin and chitosan presented the highest R-

values. The magnitude of this effect conformed to the following descending rank

order: MCC, chitosan, chitin, pregelatinized starch (PGS) and DBCP. Chitin and

chitosan were found to be potential co-excipients for direct compression applications.



Figure 1.14 Effect of compression pressure on the crushing strength of chitin, chitosan

and direct compressed reference tablets [41].

Table 1.21 Compression and compaction properties of chitin, chitosan and direct

compression reference excipients [41].

Material Tensile strength

(Mpa) R-value

(1)

Wnet

(J)

Compactibility (2)

(Mpa/J)

Chitin 64.91 0.919 4.31 15.06

Chitosan 60.19 0.921 3.74 16.10

MCC (Avicel PH 102

) 146.87 0.920 5.45 26.93

DBCP (Emcopress

) 8.96 0.679 2.62 3.41

PGS (Starch 1500) 18.16 0.726 3.18 5.72 (1)

R-value is the lubrication coefficient.

(2) Compactibility is calculated from the ratio between tensile strength and network “W net”.

1.4.6.11 Co-processed tablet excipient composed of chitin and silicon dioxide

Chitin is a water-insoluble hydrophilic polymer that can absorb water and function as

a disintegrant. Due to the unacceptable flow and compression properties of chitin,

co-precipitation with silicon dioxide was used to provide a new excipient with

excellent flow, compaction and disintegration properties when compared to the



individual components or commercially available direct compression fillers and

disintegrants. The optimal composition of the co-processed excipient contains a

silicon concentration of about 50 % w/w.

1.6 Synthetic Metal Silicates [8, 42]

Synthetic metal silicates are non toxic materials widely used in food and

pharmaceutical industry. Synthetic metal silicates i.e. “brittle materials” are good

candidates for preparing co-processed excipients when combined with chitin, a

“plastic material”.

1.6.1 Synthetic Magnesium Silicate [43]

Magnesium silicate (silicic acid, magnesium salt) is a compound of magnesium oxide

and silicon dioxide. Magnesium silicate occurs as an odourless and tasteless, fine,

white coloured slightly hygroscopic powder that is free from grittiness. Magnesium

silicate is used in oral pharmaceutical formulations and is generally regarded as an

essentially nontoxic and nonirritant material. Orally administered magnesium silicate

is neutralized in the stomach to form magnesium chloride and silicon dioxide; some

magnesium is absorbed. Magnesium silicate is listed in GRAS and accepted for use as

a food additive in Europe. It is included in the FDA regulation part 182 “Substances

generally recognized as safe” sub-part C as anti-caking agents. Also, in part 169

“Food dressings and flavourings” Subpart B – requirements for specific standardized

food dressings and flavourings.

1.6.1.1 Structural formula and composition

Magnesium silicate is a compound of magnesium oxide and silicon dioxide; it is the

magnesium salt of silicic acid containing an unspecified amount of water. Many

natural silicate minerals are formed under aqueous conditions by reactions which are

hypothesized to proceed via "protosilicate" intermediates, gels of hydrated oxides

which, in the absence of structural information, have been described as

xMgO.ySiO2.zH2O. The molecular formula may be expressed as MgSiO3.xH2O,

Figure 1.15.



xH2O

Figure 1.15 A schematic of the structure of magnesium silicate [44].

The USP/NF and JP state that the assay of magnesium silicate should be expressed as

the percentages of magnesium oxide (MgO) and silicon dioxide (SiO2). Table 1.22

shows the acceptance criteria for the content of magnesium silicate, as reported in the

USP/NF and JP.

Table 1.22 Acceptance criteria of content of magnesium oxide and silicon dioxide in

magnesium silicate [45, 46].

Component Content

USP/NF JP

MgO (%) 15.0* 20.0

SiO2 (%) 67.0* 45.0

MgO (%)/SiO2 (%) 2.50 – 4.50* 2.2 – 2.5

*Calculated on the basis of ignition.

1.6.1.2 Methods of preparation of synthetic magnesium silicate

I) Precipitation Method

The most common route for the synthesis of magnesium silicate is via the

precipitation reaction between a soluble metal silicate (e.g. sodium orthosilicate,

sodium metasilicate or potassium silicate) and a soluble magnesium salt (magnesium

sulphate, nitrate, or chloride). The aqueous suspension of the precipitate is filtered and

the collected solid washed and dried. The physical properties and magnesium oxide

(MgO) content of the precipitated magnesium silicate depend on the type of

magnesium salt, sequence of addition of magnesium salt and metal silicate, type and

concentration of dispersion modifiers (e.g. non-ionic surfactants, NaOH), and

experimental conditions. Regardless of the type of soluble metal silicates used, they

are subject to the same molecular speciation in aqueous solution resulting in a mixture



of monomeric tetrahedral ions, oligomeric linear or cyclic silicate ions and

polysilicate ions. Sodium metasilicate, an example of a soluble metal silicate, can be

prepared in anhydrous form, or with water of crystallisation as the penta- or

nonahydrate. It is readily soluble in water.

The dissolution process of sodium silicate consists of its hydration with the formation

of NaOH. Sodium orthosilicate hydrolyzes according to equation 1:

Na4SiO4 + H2O → 2NaOH + Na2SiO3 (1)

The hydrolytic dissociation is particularly strong with sodium metasilicate (equations

2 and 3):

2Na2SiO3 + H2O → Na2Si2O5 + 2NaOH (2)

Na2SiO3 + H2O → NaHSiO3 + NaOH (3)

Sodium silicate reacts with ions in solution (e.g. magnesium) forming nearly insoluble

magnesium silicates. The effectiveness of sodium silicate on precipitation of Mg2

ions when a bulk solution with magnesium chloride added to deionized water is

shown in Figure 1.16. It can be seen that the ion concentration of Mg2+

decreases

rapidly with the addition of sodium silicate.

[Sodium silicate] mM

[Mg

2io

n]

mM

Figure 1.16 Concentration of Mg2

ions, in deionized water, as a function of sodium

silicate concentration (pH 8.5) [47].

II) Hydrothermal Precipitation Method

A hydrothermal solution is a multi-component system containing compounds of Na,



K, Si, Ca, Mg, Al, Fe, Cl, S, O, C, B, Li, As, Cu, Zn, Ag, Au, and other elements in

ionic and molecular forms; Si is usually present at high concentrations. Silica,

together with other compounds, passes into this hydrothermal solution due to the

chemical interaction of water with aluminosilicate minerals of rocks of hydrothermal

fields at a depth in regions of thermal anomalies at high temperatures and pressures.

At temperatures of 250–300°C, silicon occurs in solution predominantly in the form

of individual molecules of silicic acid, H4SiO4. As a consequence, such an aqueous

solution becomes supersaturated with respect to solutions of amorphous silica in pure

water. When metal cations (e.g. Ca2+

, Mg2

and Co2+

) are introduced into the solution,

some of these ions are sorbed by the surface of colloidal particles resulting in

neutralization of the negative surface charge. Bridging bonds, with the participation of

coagulating ions, are formed between the surfaces of particles which results in

coagulation and precipitation of colloidal silica. The material precipitated by metal

ions has an amorphous structure of metal silicate. After high-temperature calcination

at 900oC, the amorphous samples prepared upon addition of magnesium sulfate or

cobalt sulfate (with simultaneous alkalization to pH 12.4) have a crystalline structure

of forsterite (Mg2SiO4) or cobalt silicate (Co2SiO4), respectively.

III) Mechano-chemical Dehydration Method

An amorphous phase can be formed as a result of the reaction of amorphous SiO2

with magnesium hydroxide. The solid-state reaction between Mg(OH)2 and SiO2

begins at the contact points between these dissimilar particles. Mechano-chemical

dehydration and amorphization of Mg(OH)2 are substantially enhanced by grinding

with SiO2. In the mixture, enhanced mechano-chemical dehydration of Mg(OH)2 is

explained by assuming the following complex processes take place: intimate mixing,

agglutination at the contact points of dissimilar particles promoted by the higher

affinity of silica over magnesia towards hydroxyl groups and initiation of

simultaneous solid-state reactions. Since magnesium hydroxide is a strong base and

silicic acid is a weak acid, acid-base neutralization ensues. A possible reaction

mechanism involves the release of excess water from the silicic acid which makes the

surface of the magnesium hydroxide more alkaline. This leads to the dissolution of

silica at the contact points, resulting in precipitation of amorphous magnesium



silicate. Thus the reaction between the two ingredients and dehydration results in a

precursor of magnesium silicate in an amorphous state.

1.6.1.3 Solubility characteristics

Magnesium silicate is practically insoluble in ethanol (95%), ether and water. It is

readily decomposed by mineral acids.

Table 1.23 shows the total amount of Mg and Si (mg/50 mL) dissolved in various

aqueous solutions (H2O, HNO3, HCl, H3PO4, and NaOH), which reflects the solubility

of magnesium silicate in these solvents. The experiment was performed by the

addition of about 0.5 g of magnesium silicate to 50 mL of solution at room

temperature (25°C) followed by incubation for 24 hours with intermittent shaking.

The total amount of Mg and Si was measured using an ICPseq-7500 spectrometer.

Table 1.23 The total amount of Mg and Si dissolved (mg/50 mL) in various solutions

at 25oC [48].

Solvent H2O HNO3 HCl H3PO4 NaOH

Conc. (M) - 0.1 1.0 3.0 0.1 1.0 3.0 0.1 1.0

Conc. of Mg and

Si dissolved in

(mg/50 mL)

0.0 5.0 12.0 20 4.0 10.0 16.0 0.0 0.0

Magnesium silicate displays low solubility in acids of up to 3 M concentration; above

this concentration it partially dissolves. It is dissociated in acids forming magnesium

ions and silicic acid in what is referred to as “acid leaching” of silicates (equation 4):

MgSiO3 + H → HSiO3

+ Mg

2 (4)

Figure 1.17 shows the conditional solubility product of magnesium silicate as a

function of pH (at an initial ion concentration of 1 mM). The region above the curve

represents a system of higher concentration product where bulk magnesium silicate

precipitation is anticipated. The higher the solution pH is the lower the conditional

solubility product, and the higher the propensity for magnesium to be precipitated.



pH

Lo

g[M

g2][

SiO

32]

Figure 1.17 Conditional solubility product of magnesium silicate (initial ion

concentration of 1 mM) as a function of pH [48].

Solubility-pH diagrams for Mg2+

-SiO32-

can be constructed to show the relationship

between Mg2+

precipitation and solution pH. For a given solution system, if the

magnesium ion concentration is above the solubility product limit, the formation of

magnesium silicate is anticipated, and is governed by equation 5:

MgSiO3(s) → Mg2

(aq) + SiO32

(aq) Ksp = 4×1012

(5)

where Ksp is the corresponding solubility product constant, which defines the

solubility limit.

According to the USP/NF, the pH of magnesium silicate (10% aqueous dispersion) is

7.0–10.8. The pH of magnesium silicate is controlled by the degree to which

magnesium is released from the surface when it comes into contact with water. The

basicity of magnesium silicate is mainly attributed to the magnesium oxide present.

1.6.1.4 Surface active sites (adsorption and absorption)

The surface of magnesium silicate is composed of free hydroxyl groups (silanol

groups); the most reactive groups on the surface. They provide the sites for the

physical adsorption of organic particles and can easily react, chemically, with

multiple substituents. Being substituted with new atom groups, they provide potential

for surface modification. The surface composition of magnesium silicate is illustrated

in Figure 1.18.



Figure 1.18 Schematic of the functional groups on the surface of magnesium

silicate [48].

The concentration of active acidic and basic sites of synthetic magnesium silicate

(Magnesol XL) is an important physicochemical characteristic which determines its

impact on adsorption performance.

1.6.1.5 Specific surface area, pore volume, and pore size

The specific surface area, pore volume, and pore size (ASAP 2010, Micromeritics

Instruments, USA), of synthetic magnesium silicate resulting from the precipitation

reaction of sodium metasilicate and a magnesium salt are dictated by the type of metal

salt, the non-ionic surfactant introduced, and the type of silane pro-adhesive

compounds used in the course of precipitation. Generally, the precipitated magnesium

silicate manifests a relatively high BET specific surface area. The highest values of

specific surface area occur with magnesium silicate produced from magnesium

sulphate and magnesium nitrate (Table 1.24). The lowest value is obtained from

magnesium chloride in the presence of Rokanol K3. The situation is analogous to

when the surface is modified using a silane coupling agent. As is the case for non-

ionic surfactants, the presence of silane decreases the specific surface area. Pore

volume and pore diameter are not affected by the presence of both reagents. The type

and amount of silane exerts no significant effect on the specific surface area, pore

volume or mean pore diameter of precipitated magnesium silicate (Table 1.25).



Table 1.24 Physicochemical properties of unmodified and modified magnesium silicates [49].

Precipit

ating

agent

Amount of non-ionic

surfactant

Modifying

agent

Amount of

modifying

agent

(wt./wt.)

Specific

surface area

BET

(m2/g)

Pore

volume

(cm3/g)

Average

pore

diameter

(nm)

MgCl2 - - - 411 0.80 5.5

5 wt/wt % of Rokanol K3 - - 197 0.67 6.3

5 wt/wt % of Rokanol K7 - - 356 0.61 7.9

Mg(NO3)2 - - - 474 0.83 5.5

5 wt/wt % of Rokanol K3 - - 347 0.87 6.2

5 wt/wt % of Rokanol K7 - - 470 0.98 7.3

MgSO4 - - - 408 0.73 5.5

5 wt/wt % of Rokanol K3 - - 433 0.85 5.6

5 wt/wt% of Rokanol K7 - - 453 0.79 5.2

MgSO4 - U-15 silane 3 401 0.68 5.2

- 5 384 0.67 5.2

- 10 332 0.63 5.2

MgSO4 - U-15 silane 3 384 0.64 4.8

5 wt/wt % of Rokanol K3 5 376 0.64 4.9

5 wt/wt % of Rokanol K3 10 364 0.67 4.8

Rokanol K3 and K7 are non-ionic surfactants (oxyethylenated unsaturated fatty alcohols, of the

general formula RO(CH2CH2O)nH R=C16-22, where nav=3 or nav=7, respectively). U-15 is silane

pro-adhesive compound (N-2-aminoethyl-3-aminopropyltrimethoxysilane).

Table 1.25 Physicochemical properties of unmodified magnesium silicate and magnesium silicate

modified with silane coupling agents [50].

Modifying agent

Amount of

modifying

agent (w/w)

Specific

surface area

BET (m2)

Pore

volume

(cm3/g)

Mean pore

diameter

(nm)

-- - 515 0.80 5.3

3-Isocynatepropyltrimethoxysilane 3 536 0.84 5.4

5 511 0.76 5.0

10 503 0.76 5.0

3-Thiocyanatepropyltrimethoxysilane 3 506 0.79 5.2

5 539 0.83 5.4

10 528 0.81 5.4

N-Phenyl-3-isocynatepropyltrimethoxysilane 3 519 0.85 5.6

5 496 0.80 5.6

10 486 0.77 3.4

1.6.1.6 Particle morphology

A scanning electron microscope (SEM) image of magnesium silicate prepared from

solutions of magnesium sulphate and sodium meta-silicate is shown in Figure 1.19.

The SEM image shows the presence of large primary agglomerates and numerous

secondary agglomerates. In addition, numerous primary particles of small diameter



are observed. Primary particles exhibit a smooth surface and no sharp edges are

observed. On the other hand, primary agglomerates of small diameter exhibit a

tendency to acquire/exhibit spherical shapes.

Figure 1.19 SEM photograph of magnesium silicate [51].

1.6.2 Preparation of Synthetic Calcium Silicate/ Synthetic Aluminium Sodium Silicate

(Precipitation Method)

Synthetic calcium silicates, aluminum silicates and magnesium silicates can be

prepared from the reaction of the aqueous solution of sodium metasilicate with the

corresponding water soluble metal salt (e.g., chloride, sulphate, etc.). This reaction

produce varying contents of sodium oxide, aluminium oxide and silicon dioxide.The

preparation procedure is shown in Figure 1.20. The content ranges of the oxides after

ignition are described in Tables, 1.22 & 1.26.

Table 1.26 Composition of synthetic calcium silicate and synthetic aluminum sodium

silicate [43, 52].

Parameter

Wt %

Aluminium sodium silicate Calcium Silicate

SiO2 42 – 85 50 – 95

Na2O 0.2 – 22 <4.0

Al2O3 0.2 – 36 --

CaO -- 1 – 35

Sulphates < 1 n.a.

Fe2O3 < 0.1 < 0.1

Trace oxides < 0.1 < 0.1



Figure 1.20 Preparation procedures for synthetic amorphous metal silicates (wet method) [52].

Dilute aqueous solution of

sodium metasilicate


calcium salt (chloride,

sulphate, etc.)


aluminium salt (chloride,

sulphate, etc.)

Solutions mixed & react in

stirred precipitation vessel

Metal silicate precipitates out as

a suspension

Precipitate undergoes filtration

via a filter press

Filter cake is washed to remove

co-product, e.g. sodium salt,

whilst in the filter press

Washed filtered cake is dried

using hot air drier

Dried material is passed through a

suitable milling sieve

Result is white, powdered metal

silicate with controlled particle

size


magnesium salt (chloride,

sulphate, etc.)

For Mg-Silicate For Ca-Silicate For Al-Silicate



1.6.3 Stability and Incompatibilities

In general, metal silicates are classified as stable compounds (Table 1.27).

Magnesium silicate exposed to temperatures of 750oC transforms from amorphous

form to the magnesium silicate minerals enstatite (MgSiO3) and forsterite (Mg2SiO4).

When the temperature reaches 1100oC and above, others polymorphs (protoenstatite

and clinoenstatite) are formed. Magnesium silicate in its solid state should be stored in

a well-closed container in a cool, dry place. When magnesium silicate is stored in

double-distilled, deionised water for 6 months at 85oC, it maintains its amorphous

structure with some improvement in the order and maintains its chemical entity.

Magnesium silicate is readily decomposed by mineral acids. Magnesium silicate may

decrease the oral bioavailability of drugs such as mebeverine hydrochloride,

sucralfate, and tetracycline, via chelation or binding, when they are taken together.

The dissolution rate of folic acid, erythromycin stearate, paracetamol, and chloroquine

phosphate, may be retarded by adsorption onto magnesium silicate. Antimicrobial

preservatives, such as parabens, may be inactivated by the addition of magnesium

silicate

1.6.4 Biodegradability and Toxicity

Orally administered magnesium silicate is neutralized in the stomach to form

magnesium chloride and silicon dioxide; some magnesium is absorbed. Caution

should be used when greater than 50 meq of magnesium is given daily to patients with

impaired renal function, owing to the risk of hypermagnesemia. Reported adverse

effects include the formation of bladder and renal calculi following the regular use,

for many years, of magnesium silicate as an antacid. It is not explosive, flammable, or

combustible. It is a mild irritant to eyes, skin, and respiratory passages. It is not

classified as dangerous under EU Directive 67/548/EEC. In the EEC, magnesium

silicate is a permitted food additive according to directive 95/2/EC (E 553a). The

essential physical and chemical properties in addition to toxicological profiles of

magnesium silicate, calcium silicate, and aluminium sodium silicate are summarized

in Table 1.27.



Table 1.27 Physicochemical properties and toxicological profile of magnesium silicate, calcium

silicate, and aluminium sodium silicate [43, 52].

Test Synthetic magnesium

silicate

Synthetic aluminum

sodium silicate

Synthetic calcium

silicate

PHYSICO-CHEMICAL PROPERTIES

CAS Number 1343-88-0 1344-00-9 1344-95-2

Chemical structure MgO.SiO2.nH2O Na2O.SiO2.nH2O/

Al2O3.SiO2.nH2O CaO.SiO2.nH2O

Form Solid powder

Melting Point [°C] Approx. 1910 (m) Approx. 1700

Partition Coefficient

(log Pow) Not relevant (inorganic , non-lipophilic substance)

Water Solubility

(Saturation) [mg/l] (m)*

Insoluble in cold and hot

water

Approx. 68 – 79 at 20 °C,

pH ~9 (Sum of soluble

SiO2, Na and Al ions)

Approx. 260 at 20 °C,

pH ~9.7 (Sum of soluble

SiO2, Na and Ca ions)

pH (m)* 7– 10.8 5 – 11 7 – 11

ENVIRONMENTAL FATE and PATHWAY

Photo-degradation Stable in water and air

Stability in Water Stable: ion exchange processes possible

Stability in Soil Stable: silicates = soil components; ion exchange processes possible

Biodegradation Not applicable, inorganic substance

Bioaccumulation Not bio-accumulating due to inherent substance properties

ECOTOXICOLOGY

Acute/Prolonged

Toxicity to Fish Not a known pollutant

96h LL0=10000 mg/l

(limit test) No data: analogy

Acute Toxicity to

Aquatic Invertebrates Not a known pollutant No data: analogy

Toxicity to Aquatic

Plants, e.g. Algae Not a known pollutant 72h NOEL= 10000 mg/l No data: analogy

TOXICOLOGY

Acute Oral Toxicity On rabbit: LD50 >10000

mg/kg LD50 >5000 mg/kg

Acute Inhalation

Toxicity Slightly hazardous No data: analogy

Acute Dermal Toxicity On albino rabbit: LD50

>10000 mg/kg

LD50 >5000 mg/kg (limit

test)

No data: analogy

Primary Irritation (skin,

eye)

On rabbit: primary

irritation index 0.80, no

erythema (skin redness)

Not irritating No data: analogy

Sensitization No data

Repeated Dose Toxicity

(inhalation)

Causes damage to lungs No data: analogy

Repeated Dose Toxicity

(oral)

No substance-related

abnormalities in rat:

NOAEL(6 months) =

~9000 mg/ kgbw

Chronic: no data: analogy

no gross signs of toxicity

in rat and mouse, no

death: NOAEL (14 d)

>5000 mg/kgbw

No gross signs of

toxicity in rat, no death

NOAEL (2 years) =

approx. 5000 mg/kgbw



Table 1.27 (continued)

Test Synthetic magnesium

silicate

Synthetic aluminum

sodium silicate

Synthetic calcium

silicate

Genetic Toxicity in Vitro

A. Bacterial Test

(Gene mutation) Not mutagenic No data: analogy Not mutagenic

B. Non-Bacterial In-

Vitro Test (Gene

Mutation) Not mutagenic No data: analogy No data: analogy

C.

Non-Bacterial In-

Vitro Test

(Chromosomal

Aberration)

Not mutagenic No data: analogy Not mutagenic

Genetic Toxicity in-

Vivo Not mutagenic No data: analogy Not mutagenic

Carcinogenicity

(inhalation) Inconclusive No data

Carcinogenicity (oral) Not carcinogenic in rat

and mouse No data: analogy Not carcinogenic in rat

Carcinogenicity

(intrapleural) No data: analogy Not carcinogenic in rat No data: analogy

Toxicity to Fertility No effects in limited

study in rat No data: analogy

Developmental /

Teratogenicity

No adverse effects in rat,

mouse, rabbit and hamster


mouse, rabbit and hamster


mouse, and hamster

Photo-degradation Stable in water and air

Stability in Water Stable: ion exchange processes possible

Stability in Soil Stable: silicates = soil components; ion exchange processes possible

Biodegradation Not applicable, inorganic substance

Bioaccumulation Not bio-accumulating due to inherent substance properties

1.6.4 Applications

Due to their inert nature and non-toxic properties, metal silicates are widely used in

different applications including cosmetics, pharmaceuticals, foods, chromatography,

rubber, paints, paper and plastic industries (Table 1.28).



Table 1.28 Applications of metal silicates in various industries [43, 52].

Industry Function

Pharmaceutical Synthetic magnesium silicate is used in oral pharmaceutical formulations and food

products as a glidant and an anti-caking agent while calcium silicate is widely use as filler

and disintegration promoter in tablet formulation [53]. Other uses of metal silicates can be

summarized as follows.

Magnesium silicate and aluminium silicate are used in anti-acid, anti-ulcer and anti-

obesity preparations.

Magnesium silicate is used as a component of anti-epileptic drugs, in the treatment

of alimentary intoxication, indigestion and in the inflammatory conditions of the

small intestine.

In topical preparations, magnesium silicate is used as anti-fungal agent.

Magnesium sodium silicates are used in cosmetics especially in toothpastes, gels,

facial creams, body washes, cosmetic creams, sunscreens, shampoo, and blush.

Magnesium sodium silicate is also used in treatment of acne and function as facial

moisturizer.

Arginine silicate (The reaction product of arginine and magnesium silicate) is highly

soluble in water and can be used as source of the essential amino acid arginine and

as a source of silicate, both of which exert anti-atherosclerotic effects and also

promotes bone and cartilage formation in mammal.

Food Metal silicates function as a carrier for fragrances or flavors. They are also used in beer and

wine clarification. In animal feed, synthetic amorphous silica and silicates serve as carriers

and anti-caking agents in vitamins and mineral premixes. Synthetic magnesium silicate and

calcium silicate are used as bleaching agent in animal and vegetable oils production. It is

also used in the production of confectionery as an anti-adhesive and anti-caking agent

(molding powder or a component of anti-glitter paste). As far as whiteness is concerned,

the white color of magnesium silicate may easily compete with titanate based pigments,

which eliminates partially or totally the use of titanium dioxide.



Table 1.28 (continued)

Industry Function

Rubber and

Silicones

Magnesium silicate, calcium silicate and aluminum silicate are used as reinforcing fillers

for many non-staining and colored rubber and silicones products.

Paints Magnesium silicate and aluminum silicate can be used as filler and pigment in dispersive

paints.

Chromatography Magnesium silicate is used as an adsorbent in affinity chromatography.

Paper Magnesium silicate and aluminium silicate are used as filler in paper manufacturing to

improve printability and opacity that result in glossy paper used in most magazines.

Insecticide, micro

biocide &

fungicide

Magnesium silicate has been used against juvenile and adult store product pests,

predominantly exerting their lethal activity on juvenile and adult forms by sorption of the

cuticular lipid layer, thus causing dehydration of the insects.

Cements Cement is made by forming a calcium silicate product from limestone and clay minerals

in a kiln which requires very hot temperatures, releasing high levels of CO2 as it burns.

Most low carbon cements on the market are based on magnesium silicate, which takes less

energy to heat.

Other uses Sodium silicate together with magnesium silicate is used in muffler repair and fitting

paste. When dissolved in water, both sodium silicate, and magnesium silicate form a

thick paste that is easy to apply. When the exhaust system of an internal combustion

engine heats up to its operating temperature, the heat drives out all of the excess water

from the paste. The silicate compounds that are left over have glass like properties,

making a temporary brittle repair.

Highly dispersed magnesium silicates can be used as polymer fillers or active

adsorbents.

Magnesium silicate is an amphoteric compound with a huge specific area capable of

absorbing either acid or alkali metal catalyst. It is an efficient refining and purifying

agent in the production of polyols for its excellent depicking, deodorizing, potassium

ion absorbing effects and function as filter medium. In addition it is used as an

adsorbent to regenerate frying oils and purify biodiesel.

Magnesium silicate, aluminium silicate and calcium silicate are used as filler and

pigment extender in fingernail lacquers and in plastic industries.

http://en.wikipedia.org/wiki/Magnesium_silicate

http://en.wikipedia.org/wiki/Muffler

http://en.wikipedia.org/wiki/Exhaust_system

http://en.wikipedia.org/wiki/Operating_temperature



1.7 Sugar Alcohols

Sugar alcohols are brittle materials having unique physicochemical properties. They

are ideal candidates for the co-processing with chitin to produce an excipient with

improved physical properties. Sugar alcohols are carbohydrates which are also called

"polyols". Part of their chemical structure resembles sugar, and part of it resembles

alcohol hence the name is sugar alcohol. Examples of common sugar alcohols are

mannitol, maltitol, sorbitol, isomalt, and xylitol. They occur naturally in plants

(sorbitol is extracted from corn syrup and mannitol from seaweed), but they are

mostly manufactured from sugars and starches. Sugar alcohols are not completely

absorbed by the body like sugars. Because of this, the blood sugar impact of sugar

alcohols is less and they provide fewer calories per gram [54, 55].

Table 1.29 Comparison of the properties of sugar and sugar alcohols.

Ingredient Sweetness (relative to

sucrose) %

Glycemic

Index (GI)

Cal/g Derived from

Sucrose (sugar) 100 60 4 Plant sources (sugar

beets, sugar cane,..)

Hydrogenated Starch

Hydrolysate

33 39 2.8 Partial hydrolysis of

starch

Maltitol 75 36 2.7 High maltose corn syrup

Xylitol 100 13 2.5 D-xylose

Isomalt 55 9 2.1 Sucrose

Sorbitol 60 9 2.5 Glucose

Lactitol 35 6 2 Lactose

Mannitol 60 0 1.5 Fructose

Erythritol 70 0 0.2 Glucose

Additionally, sugar alcohols don't induce tooth decay as sugars do, so are often used

to sweeten chewing gum. Sugar alcohols have fewer calories than sugar, and most of

them are less sweet than sugar except for xylitol which have the same sweetening

factor [54]. The glycemic index is an indicator of how a food is likely to affect blood

sugar (Table 1.29).

1.7.1 Mannitol: sugar alcohol with added functionality

Mannitol is a naturally occurring six-carbon sugar alcohol or polyol (Figure 1.21)

[56]. It is the most abundant polyol in nature occurring in bacteria, yeasts, fungi,

algae, lichens and several plants like pumpkins, celery, onions, grasses, olives and

mistletoe. Mannitol (C6H14O6) is widely used in pharmaceutical formulations and food

products [57]. In pharmaceutical preparations it is primarily used as a diluent in tablet

http://lowcarbdiets.about.com/od/glossary/g/glosstermcarb.htm

http://en.wikipedia.org/wiki/Hydrolysis

http://en.wikipedia.org/wiki/Starch



formulations, where it is water soluble, non-hygroscopic (Can be used with moisture-

sensitive active ingredients) and produces a sweet, smooth, cool taste and it can be

advantageously combined with other direct compression excipients.

Figure 1.21 Chemical structure of mannitol [56].

In ODT formulation, the direct compression grade of mannitol is prefered to obtain a

fast disintegrating hard tablets withstand processing and transportation. Specially

treated directly compressible, spray-dried, or granulated mannitol excipients have

been designed to meet these needs. Figure 1.22, shows the scanning electron

microscopic images of granular, powder and spray dried mannitol.

Processing of treated mannitol (Figures 1.22.a and 1.22c) produced under defined

manufacturing conditions give them a highly porous and friable external particle

structure. Upon compression, the particles break into finer particles, which fill the

interstitial spaces between larger porous particles which give harder ODTs using

direct compression at low pressure.

Figure 1.22 SEM images of a) granular mannitol, b) mannitol powder and c) spray-

dried mannitol [56].



Untreated crystalline mannitol has some limitations including the poor aqueous

solubility, bad flowability and the high friability of tablets obtained. Figure 1.23,

shows the water solubility of mannitol in comparison with other excipients.

Figure 1.23 The aqueous solubility of mannitol versus other excipients [58].

Figures 1.24, 1.25 and 1.26 show the physical properties of different types and grades

of mannitol.

Figure 1.24 Tablet compression profiles of different grades of mannitol [58].



Figure 1.25 Friability versus compression profile for different grades of mannitol [58].

Figure 1.26 Moisture sorption profiles of different sugar alcohols at 20C [58].

One major limitation of most currently marketed ODTs is their requirement for

special and expensive packaging to protect them during transportation and handling.

Furthermore, the consumer must follow specific instructions to remove fragile tablets

from specialized blister packs to ensure added protection and to retain the quick

dispersibility of the tablets even after exposure to unfavorable humidity and

temperature conditions. These challenges could be addressed by [58]:

Using binders with the mannitol powder may increase the disintegration time of

the ODT and accordingly disintegrant(s) should be added to reduce the

disintegration time.

Co-processing of mannitol with other excipients or material is a way to create

an excipient that exhibits a flowability and compressibility. Additionaly, the

slow disintegration properties of mannitol can be significantly improved by

the right selection of the co-processing candidate.



1.7.1.1 Toxicology

Mannitol is GRAS listed material. The use of mannitol in food is permitted by FDA

food additive regulations (21 CFR 180.25). The Joint Food and Agriculture

Organization/World Health Organization Expert Committee on Food Additives

(JECFA) has reviewed the safety data and concluded the safety of mannitol. JECFA

has allocated an acceptable dietary intake of 0-50mg/kg. Mannitol has monographs in

the United States Pharmacopoeia/National Formulary (USP/NF), as well as the

various pharmacopoeias around the world. In addition, mannitol is included in the

Food Chemical Codex (FCC) [56, 59].



1.8 Project: Hypothesis, Aims and Work Plan

1.8.1 Hypothesis

In powder form, chitin is a highly compressible material due to the presence of pores

on the surface and it is a well known disintegrant for tablet formulation [42].

However, chitin is not compactible. It would be beneficial, therefore, to form

inclusion complexes of guest material inside the chitin pores to improve its

compactibility without affecting its disintegration properties.

1.8.2 Aims

Improvements in the compaction properties of chitin by co-processing with a guest

material could be verified as follows:

- co-processing of chitin with metal silicates, by incorporating the metal silicate inside

the chitin pores, could produce a multi-functional super-disintegrant (excipient that

can achieve fast disintegration while preserving the binding properties of the tablets).

- by examining the effect of lubricant on powder compaction of co-processed

chitin-metal silicate excipients.

- co-processing of chitin with mannitol (as an example of a compound representing a

non-hygroscopic inert excipient) could result in a universal multi-functional excipient

that could be used with metal-incompatible active pharmaceutical ingredients.

1.8.3 Work Plan

(I) To study the physicochemical properties, performance and applications of the co-

precipitates of chitin and metal silicates prepared according to European patent

(EP1997480) invented by the Jordanian Pharmaceutical Manufacturing CoLtd

(Chapters 2&3). This work covers the following aspects.

Preparation of a solid in solid dispersion of metal silicate within the chitin

pores. The procedure followed was that in European Patent (EP1997480), by

dispersing the chitin polymer and an appropriate quantity of monovalent



silicate in sufficient quantity of water or a mixture of water and solvent(s).

Precipitation of the mineral silicate within the structure of the polymer can be

achieved by the addition of a divalent or trivalent chloride solution to form a

solid in solid dispersion of mineral silicate within the chitin high surface

pores. The divalent or trivalent chloride solution can be magnesium chloride,

calcium chloride, aluminum chloride, etc.

Preparation of different grades of the silicate-chitin material (different salts)

with respect to the particle size and physical properties. In addition to study

the effect of these properties on the performance of this material.

Characterization and identification of the obtained chitin silicates (different

salts) using different analytical techniques such as scanning electron

microscopy, x-ray powder diffraction, powder flow analysis, FTIR

spectroscopy, NMR, etc.

Investigate the prepared co-precipitated excipient properties including the

compactibility, flowability and density.

Testing the physical properties of the tablet formulations containing the co-

precipitated excipient such as compressibility, granules flowability and

disintegration properties will be evaluated in comparison with reference

formulations containing commercially available super-disintegrants such as

sodium starch glycolate, pregelatinized starch, PVP-XL and croscarmelose

sodium.

Designing tablet formulations containing the co-precipitated chitin-metal

silicate excipient using different techniques including, direct compression, wet

and dry granulation. The co-processed excipient functionality, compatibility

with APIs and compression profiles of the tablets produced will be evaluated.

Determination of the recommended working range(s) of the silicate-chitin

material, which can be used in solid state pharmaceutical formulations in order

to attain the optimal function as a super-disintegrant and pharmaceutical aid in

tablet formulation.

Investigate the effect of lubricant on the overall physical properties of the

co-precipitated chitin-metal silicate excipient.



(II) To study the physicochemical properties, performance and applications of the co-

processed excipients consisting of chitin and mannitol prepared according to the

European patent (EP2384742) invented by the Jordanian Pharmaceutical

Manufacturing CoLtd (Chapters 3 & 4) This work covers the following aspects.

Preparation of a co-processed excipient consisting of chitin and mannitol by

following the procedure as in the European Patent (EP2384742). Two types of

excipients were prepared according the formentioned patent including: i) a

multifunctional immediate release tablet base (Chapter 4) and ii) an ODT

multifunctional base (works as disintegrant, binder, filler) (Chapter 5).

Optimizing the ratio of chitin and mannitol within the co-processed excipient

and selecting the proper processing technique to be used.

Characterization and identification of the prepared co-processed excipients

using different analytical techniques such as scanning electron microscopy, x-

ray powder diffraction, powder flow analysis, FTIR spectroscopy, NMR, etc..

Characterization of the obtained excipients regarding the physical properties

including flowability, compressibility, functionality, disintegration and

wetting properties.

Evaluation of the tablets prepared from the co-processed chitin-mannitol

excipients.

Studying the applications of the obtained co-processed excipients in tablet

formulation containing different APIs.

1.9 References

[1] Shireesh P. Apte, Sydney O. Ugwu. Emerging Excipients in Parenteral

Medications: The New Paradigm. In: Katdare A, Chaubal MV, editors. Excipient

development for pharmaceutical, biotechnology, and drug delivery systems. New

York, London: Informa healthcare; 2006.

[2] Harold Davis. Food and Drug Administration Perspective on Regulation of

Pharmaceutical Excipients. In: Katdare A, Chaubal MV, editors. Excipient


York, London: Informa Healthcare; 2006.



[3] Lokesh Bhattacharyya, Stefan Schuber, Catherine Sheehan, and Roger William.

Excipients: Background / Introduction. In: Katdare A, Chaubal MV, editors. Excipient


York, London: Informa healthcare; 2006.

[4] Fred J. Bandelin. Compressed Tablet by wet granulation. In: Lieberman HA,

Lachman L, Schwartz JB, editors. Pharmaceutical dosage forms: Tablets, Volume 1,

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CHAPTER TWO


2. CHARACTERIZATION OF CHITIN–METAL SILICATES AS

BINDING SUPER-DISINTEGRANTS

2.1 Introduction

There is increasing interest in exploring new commercial uses for chitin, a polymer

which is normally regarded merely as a waste product from, for example, the sea food

industries. This is due to the fact that, next to cellulose, chitin is the most abundant

polysaccharide on earth [1]. In relation to the pharmaceutical industry; chitin has been

reported to play different roles in tablet formulations, for example, as an excipient for

direct compression and as a disintegrant [2, 3]. However, for many pharmaceutical

formulations there is a need to improve compression properties in order to make them

acceptable to the formulator [4, 5]. Recently, chitin was modified by precipitation of

silicon dioxide on its surface [6]. The foregoing concept was based upon the high

water absorption capacity and surface modification properties of silicon dioxide when

co-processed with polymers [7, 8]. Co-precipitation of silicon dioxide onto chitosan

or chitin particles resulted in high mechanical strength of compacts with super-

disintegration properties [6]. When modified in this manner, tablet disintegration was

characterized by superior water uptake and penetration, with no gelling hindrance

effects; this makes silicon dioxide different from other known super-disintegrants.

However, there are disadvantages associated with silicon dioxide polymer

preparations. For example, co-precipitation of colloidal silicon dioxide onto chitin or

chitosan particles involves the use of large volumes of concentrated hydrochloric acid

and sodium hydroxide solutions not to mention high temperature [6, 9]. This imposes

a high cost burden during industrial processing. Furthermore, the disintegration

properties of chitin–silica powder are strongly dependent on its compactability.

Finally, the chitin–silica particles are highly hygroscopic at humidity conditions above

70% RH. Such drawbacks necessitated an exploration of the use of an alternative

industrial processing strategy. We hypothesized that metal silicates could represent a

suitable alternative to silicon dioxide. In fact, metal silicates have been tested as

disintegration promoters (Rxcipients FM 10001 application bulletin). Specifically, the

use of amorphous synthetic calcium silicate (Rxcipients FM10001) has been

advocated; one reason for calcium silicate’s potential as a fast disintegrant may be its

CHAPTER TWO


highly porous nature. It has been found that the combined use of calcium silicate, in

concentrations up to 30% (w/w), with super-disintegrants, provides acceptable tablet

hardness whilst concomitantly allowing rapid tablet disintegration; in less than 30 s in

the mouth [10]. The combined use of chitin and metal silicate could fulfill the dual

role of superdisintegrant and filler in pharmaceutical formulations. However, it is well

documented that commercially available super-disintegrants lose their function as

disintegrants when their concentration exceeds certain limits (3–15%, w/w) [9].

Therefore, their use as fillers or binders in solid dosage form formulations could be

deleterious. Chitin exhibits super-disintegration properties that depend, mainly, upon

a high water uptake rate, [3] so it can be presented over a higher concentration range

compared to other commercial super-disintegrants without affecting the disintegration

properties [6, 9]. However, chitin shows poor powder compressibility [11].

Ultimately, the combination of one of the most abundant naturally occurring polymers

with metal silicates could represent a practical and invaluable choice of an industrial

excipient in terms of disintegration and compaction properties. In this regard, if co-

precipitation is the desired methodology to ensure an effective distribution of silicon

dioxide onto chitin particles, then replacing silicon dioxide with an insoluble metal

silicate should be considered. Indeed poor (aqueous) solubility is a useful property for

a disintegrant and it just so happens that this is a general characteristic of most metal

silicates, except for sodium silicate [12, 13]. Therefore, it was hypothesized that by

carrying out a simple chemical displacement reaction, that is, by adding a soluble salt

of the appropriate metal to a sodium silicate solution in which chitin particles are

suspended, an insoluble metal silicate could be produced. Thus, chitin particles could

provide the surface on which metal silicate precipitation takes place. The work

reported herein aims to test such an assumption as well as to characterize the resulting

co-precipitates produced using different metal silicates and its utilization as a super-

disintegrant and a single component additive in immediate release tablets.

CHAPTER TWO


2.2 Experimental

2.2.1. Materials

Chitin (200 mm, JBICHEM, Shanghai, China), Avicel® 200 (FMC BioPolymer,

Philadelphia, PA), Na2SiO3.5H2O (BDH, Poole, England), AlCl3.6H2O (MERCK

KGaA, Darmstadt, Germany), MgCl2.6H2O (SIGMA Chemical Co, St. Louis, MO),

CaCl2.2H2O (ACROS Organics, Geel, Belgium), paracetamol (Sri Krishna

Pharmaceutical Ltd, Hyderabad, India), metformin HCl (Hercules Plaza, Wilmington,

DE), mefenamic acid (Shinpoong Pharma, Seoul, Korea), PonstanTM Forte 500 mg

tablets (Chemidex Pharma Ltd, Surrey, UK). All reagents used were of analytical

grade.

2.2.2 Methods

2.2.2.1. Preparation of Metal silicate-Chitin powder

Into three separate solutions, each containing 10.0 g of sodium silicate dissolved in

400 mL of deionized water, 7.5, 10, and 11.5 g of chitin were suspended under

stirring conditions. Respectively, 6.0 g of aluminium chloride, 9.6 g of magnesium

chloride, 6.9 g of calcium chloride were added to stochiometrically react with sodium

silicate to produce suspended particles of the insoluble metal silicate that co

precipitated onto chitin. The particles were filtered out using 20-25 m filter papers

(ALBET 135, Quantitative, Barcelona, Spain) then washed with deionized water until

the filtrate conductivity, measured using a conductivity meter (METTLER TOLEDO

MPC227, Greifensee, Switzerland), was less than 20 S. The product was dried in the

oven at 90ºC for 3 hours, and finally passed over a mesh of 425µm size and kept for

further testing and characterizations of the obtained material. The final Al, Mg, and

Ca silicate mass content was fixed at 32% (wt/wt).

2.2.2.2 FT-IR Spectroscopy

Infrared spectroscopy was used to follow the molecular interaction between chitin and

the metal silicates. For Fourier transform infrared spectroscopy (Perkin–Elmer,

Buckinghamshine, UK), Al silicate, Mg silicate, Ca silicate, their corresponding

CHAPTER TWO


co-precipitates with chitin particles, a physical mixture of chitin and magnesium

silicate, with a Mg silicate content of 32% (w/w), and chitin were all separately mixed

with dried KBr (1%, w/w). Then a small portion of the mixture was compressed in a

15 mm dye at 1 × 105 kPa to yield a transparent disk. The disk was mounted in the

instrument beam for spectroscopic examination.

2.2.2.3. X-ray diffraction

The XRPD patterns of Al, Mg, and Ca silicates, their corresponding chitin particle co-

precipitates chitin, a physical mixture of chitin and magnesium silicate at a Mg

silicate content of 32% (w/w), and chitin, were all investigated using an X-ray

diffractometer (Philips PW 1729 X-Ray Generator; Philips, Eindhoven, the

Netherlands). XRPD spectra were acquired on a Scintag Pad V X-ray Powder

Diffractometer using CuKα radiation on a – 2 goniometer equipped with a

germanium solid-state detector, using acquisition conditions of 35 kV and 30 mA.

Scans were typically obtained from 10 to 70 2, with step size or integration range of

0.05, and a count time of 5 s.

2.2.2.4. Scanning electron microscopy

Chitin and chitin–Mg silicate samples were mounted on aluminum stubs and then

coated with gold by sputtering at 1200 V, 20 mA for 105 s using a vacuum coater. A

FEI Quanta 200 3D SEM (FEI, Eindhoven, The Netherlands) instrument was used.

2.2.2.5 Water penetration rate

Chitin-Mg silicate and Avicel® 200 were separately poured into graduated cylinders.

In order to visualize and measure the water penetration into the samples, 50 mL of

0.1% (wt/vol) of sunset yellow solutions were prepared and added on top of each of

the chitin-Mg silicate and Avicel® 200 samples. The penetration rate was calculated

by measuring the speed of water in mL/min penetrating the samples column. This

method was validated upon changing the dye concentration (0.1-1%), dye solutions

added volume (10-100 mL) and the samples volume (50-200 mL). This test was

performed at the following powder particle size of 125, 300, 710, 1400 μm for chitin-

CHAPTER TWO


Mg silicate and Avicel® 200. In order to obtain different particle size of Avicel

® 200

(particle size was 180 μm) and chitin-Mg silicate (particle size of 425 μm), initially

each powder was compressed into 12 mm circular tablets and then the tablets were

crushed in a dry granulator (Erweka TG IIS) coupled to a Erweka AR 400

multipurpose motor (Erweka GmbH, Heusenstamm, Germany) to obtain granules

with a particle size < 2.00 mm. Finally, the slugs were ground manually, using a

pestle, over separate sieves of mesh particle size 125, 300, 710, 1400 μm.

2.2.2.6 Chitin-Mg silicate hygroscopicity

Different samples of chitin–Mg silicate (initial weight of 2.0 g) were stored in

desiccators containing saturated salt solutions at room temperature for a week. The

media compositions were set according to the Handbook of Chemistry and Physics

[14]. Samples were stored in desiccators under equilibrium conditions for one week.

The percentage gain in weight compared to the original weight was measured for each

humidity setting.

2.2.2.7 Water infiltration rate

Infiltration of water into the chitin, chitin-Mg silicate, Mg silicate, and Avicel® 200

powders at tap density was performed in capillary rise experiments [15]. Each powder

was poured into a glass tube supported by a clamp attached on top of a beaker

containing a reservoir of water. The water was once more dyed with sunset yellow

solution to visualize the ascending water from bottom to top of the tube. A glass wool

was placed at the bottom of the tube to allow water to pass while supporting the

powder. The tube was lowered in the beaker up to the point that the fluid level

reached the top of the glass wool. Time zero was chosen when the liquid first meets

the powder. The infiltration rate was calculated by measuring the speed of ascending

water in mL/min penetrating the samples column from bottom to top.

2.2.2.8. Particle size influence on disintegration and hardness measurements of

chitin-Mg silicate

Chitin-Mg silicate granules were initially produced by co precipitation and then

ground manually (using a pestle) over separate sieves, after drying, of mesh particle

CHAPTER TWO


size 1400 μm, 425 μm, and 125 μm. Each of the three powder samples of specific

particle size was subjected to compression using a single punch tableting machine

(Manesty, Merseyside, UK) at the compression forces 30, 35, 40, 45, and 50 KN, in

which a 12 mm circular punch was fitted, producing tablets of 400 mg weight. Tablet

hardness and disintegration time were examined for all tablets produced at each

compression force. Tablet hardness was measured using a hardness tester (Copley,

Nottm Ltd, Therwil, Switzerland), whereas disintegration time was measured using a

disintegration tester (Caleva, Dorset, UK). The average hardness and disintegration

readings of 10 tablets were considered for each particle size at the specific

compression force.

2.2.2.9 Mass content influence of metal silicates on tablet hardness and

disintegration time

For chitin-Al silicate samples preparation: 7.5, 11.2, 15, 22.6, and 30.1 g of chitin

were respectively suspended in five separate solutions, each containing 10 g of

sodium silicate dissolved in 400 mL of deionized water. 6 g of aluminum chloride

were added to each of the chitin suspensions to ensure complete precipitation of Al

silicate. The method was repeated using same concentration of sodium silicate

separate solutions containing 10, 15, 20, 30, and 40 g of chitin for chitin-Mg silicate

and 11.5, 17.2, 23, 34.6 g of chitin for chitin- Ca silicate preparations. 9.6 g of

magnesium chloride and 6.9 g of calcium chloride were respectively added to each of

the chitin suspensions. All the resulted chitin-metal silicate suspensions were filtered

out, washed with deionized water, dried in the oven at 90ºC for 3 hours, and finally

passed over a mesh of 425µm size. All the samples produced were compressed using

the single punch tabletting machine in which a 12 mm circular punch was fitted,

producing tablets of 400 mg weight. Tablet hardness and disintegration time were

measured for each tablet. An average of 10 tablets was considered for each test. The

percentage content of metal silicate for the prepared samples was calculated as

follows: 32, 23.9, 19.0, 13.5, 10.5 % (wt/wt).

2.2.2.10. Characterization of the compression process of chitin–metal silicate

Chitin, chitin-Al silicate, chitin-Mg silicate (at the Mg silicate contents of 13, 19, 24,

CHAPTER TWO


32 % (wt/wt) in the chitin-Mg silicate compacts) and chitin-Ca silicate were

separately compressed by direct compressing using the universal testing machine

(UTM, RKM 50, PR-F system, ABS Instruments Pvt., Ltd., Leipzig, Germany). This

was achieved without lubrication of the upper and lower punches as well as the die.

The punch speed was fixed at 10 mm/min. Different compression forces from 80 to

390 MPa were applied. Three tablets were prepared to ensure reproducibility. The

tablets were flat, round of 12 mm diameter and 400 mg weight.

The compression behavior of the samples was evaluated using the Kawakita analysis

of powder compression data. The Kawakita equation (Equation 1) is used to study

powder compression using the degree of volume reduction, C. The basis for the

Kawakita equation for powder compression is that particles subjected to a

compressive load in a confined space are viewed as a system in equilibrium at all

stages of compression, so that the product of the pressure term and the volume term is

a constant [16]:

C = [V0 – V/V0] = [abP/1 + bP] (1)

Where, C is degree of volume reduction, V0 is the initial volume, V is the volume of

powder column under the applied pressure P. The constant, a is the material’s

minimum porosity before compression while the constant b relates to the material’s

plasticity. The reciprocal of b defines the pressure required to reduce the powder bed

by 50% [17, 18]. The equation above can be re arranged in linear form as:

P/C = P/a + 1/ab (2)

The expression of particle rearrangement could be affected simultaneously by the two

Kawakita parameters a and b. The combination of these into a single value, i.e. the

product of the Kawakita parameters a and b, may hence be used as an indicator of the

expression of particle rearrangement during compression [19].

2.2.2.11. Formulations using chitin-Mg silicates

The composition and the type of formulation process (direct compression and wet

granulation) of formulas containing paracetamol, metformin HCl, and mefenamic acid

are listed in Table 2.1. Formulas F1, F3, F4, F6, and F7 were formed by direct

compression, whereby the lubricant was initially passed through a 200 μm sieve, all

the other components were mixed using an Erweka mixer (Erweka AR 400,

CHAPTER TWO


Heusenstamm, Germany), then passed through a 0.8 mm sieve and finally the

lubricant was added to the mixture. For the case of wet granulation, purified water

was used as the granulating fluid of formulations F2 and F5 using a graduated

measuring cylinder. The wetted granules were passed through a 2.5 mm sieve. The

granules were dried in a hot-air oven at 40 °C for 1 hour. The dried granules were

passed through a 0.8 mm sieve. Finally, the lubricant (magnesium stearate) was added

to the mixture. All formulas were compressed using a single punch tabletting machine

(Manesty F3 single stroke tablet press, West Pharmaservices Ltd, Dorset, UK) in

which a 13 mm shallow concave punch was fitted. Compression was carried out using

a load of 40 KN.

Table 2.1 Composition of paracetamol, metformin HCl, and mefenamic acid tablets

formulations.

Formula

No. Drug

Manufacturing

Process

Active

Ingredient

(mg)

Chitin-

Mg

Silicate

Quantity

(mg)

Calcium

Silicate

Quantity

(mg)

Magnesium

Stearate

Quantity (mg)

1 Paracetamol Direct

Compression 500 385 -- 2

2 Paracetamol Wet Granulation 500 385 -- 2

3 Paracetamol Direct

Compression 500 -- 358 2

4 Metformin HCl Direct


5 Metformin HCl Wet Granulation 500 375 -- 5

6 Metformin HCl Direct

Compression 500 -- 375 5

7 Mefenamic Acid Direct


8 Ponstan

Forte

500 mg -- 500 -- -- --

For hardness and disintegration testing, an average of 20 tablets from each formula

was considered using the hardness and disintegration testers respectively. For drug

dissolution, an average of 8 tablets was considered using the USP specifications of the

CHAPTER TWO


dissolution media and apparatus for each drug [20]. PonstanTM

Forte 500 mg tablets

were used for comparison purposes with formula F7 of mefenamic acid with respect

to hardness, disintegration and dissolution in its designated USP media

2.3 Results and Discussion

Metal ions react with silicate ions and form insoluble metal silicates [21].

Accordingly, co-precipitation of Al, Mg and Ca silicate followed the following

reactions:

2AlCl3 + 3Na2SiO3 Al2(SiO3)3 + 6NaCl

MgCl2 + Na2SiO3 MgSiO3 + 2NaCl

CaCl2 + Na2SiO3 CaSiO3 + 2NaCl

Consequently, the soluble sodium silicates changed to larger molecules of metal

silicates that precipitated onto chitin. The pH of the compacts (5% (w/v) aqueous

dispersion) resulting from the co- precipitation of Ca, Mg, and Al silicates onto chitin

particles was measured as 10.5, 8.5, and 6.0 respectively. All these metal silicates are

composed of silicon dioxide (Ksp of 10-3

in water) linked randomly to the metal oxide

which has a degree of solubility that depends on the type of metal. In water, these

metal oxides are characterized by the solubility product constant Ksp of metal

hydroxide which has the values of 5.0x10-6

, 6.0x10-12

, and 3.0x10-34

for Ca, Mg, and

Al hydroxides respectively. The Ksp for the Al(OH)3 is the lowest of all, thus the

acidic nature of Al silicate is mainly attributed to the silicon dioxide which is very

slightly soluble in water and acidic in nature. Alternatively, Ca and Mg silicates

basicity is mainly attributed to the metal Ca and Mg oxides present [22, 23]. The

nature of chitin-metal silicate association resulting from the co-precipitation process

was investigated using FTIR and x-ray diffraction analysis.

CHAPTER TWO


Wave number (cm-1

)

Figure 2.1 FTIR of Al, Mg, Ca silicates prepared by precipitation of the metal

silicates through replacement reaction of sodium meta-silicate with

the metal chlorides.

Infrared spectra of the prepared precipitates of Al silicate, Mg silicate, and Ca silicate

are shown in Figure 3.1. All these metal silicates showed common IR features with

respect to the absorption band at 1039 cm-1

which is due to a Si-O-Si symmetrical

stretching vibration. In addition, the Si-O bending vibration of the metal silicate can

be observed at 432 cm-1

in the spectrum. The other bands in the spectrum around 654

cm-1

and 3450 cm-1

are probably associated with various metal-O modes and water

molecules, respectively [24]. However, Ca silicate had two distinctive bands in the

1400-1480 cm-1

region that can be assigned to the O-H bending mode [25] .These two

bands were not present in the Al and Mg silicates. In general, the cation

electropositivity and ionic radius play important roles in the stretching and bending

modes, respectively [26]. On the other hand, chitin (Figure 2A) showed split

absorption bands at 1660 and 1620 cm-1

corresponding to the amide I region (C=O

stretching ) and an absorption band at 1560 cm-1

corresponding to the amide II region

(N-H bending vibrations) [27].

CHAPTER TWO


Wave number (cm-1

)

Figure 2.2 FTIR of chitin, chitin-metal (Al, Mg, Ca) silicate co-precipitates, and

chitin-Mg silicate physical mixture.

All these bands were identical in both chitin and chitin-metal silicate co-precipitates

on the one hand (Figures 2.2B, C, & D for chitin-Al, Mg, and Ca co precipitates

respectively), and chitin-Mg silicate physical mixture (taken as an example of a

chitin-metal silicate) on the other (Figure 2.2E). This suggests no chemical reactivity

is present between chitin and all the tested metal silicates when the later underwent

co-precipitation. The difference between the co-precipitate (Figures 2.2B, C, & D)

CHAPTER TWO


and the physical mixture (Figure 2.2E) could be clearly demonstrated by the

sharpness of the peaks of the physical mixture and the broadness of the peaks of the

co-precipitate. It seems that this difference is related to the precipitation of Mg silicate

onto the chitin surface. The silanol groups, which are known to have a hydrogen

bonding potential with some substances, [28] present on the surface of Mg silicate

could attribute to the broadening of IR peaks of both chitin and Mg silicate for the co

precipitate. Generally, the impact of hydrogen bonding is to produce significant band

broadening and to lower the mean absorption frequency [29]. The investigated chitin-

metal silicates co precipitates and their physical mixtures were tested using x-ray

diffraction in order to evaluate the role of co precipitation on crystallinity. The x-ray

diffraction patterns of synthetic Al, Mg, and Ca silicates produced by the reaction of

sodium silicate with their corresponding metal salts are presented in Figure 2.3. In

general, the term ‘silicate’ refers to crystalline materials with known composition.

However, Al and Mg silicates clearly showed amorphic characters with broad peaks

all over the diffraction pattern range. A fairly more ordered pattern was noticed for Ca

silicate, which showed a distinctive broad peak at 30º 2θ. This suggests that Ca

silicate could have a little more than a two-dimensional short-range order [30]. Such

crystallographic diversities of metal silicates could be attributed to the fact that

different alkaline cations favor different structures. More specifically, the crystalline

lattice structure of different metal silicates is dependent upon the type, size and atomic

weight of the metal cation which defines the orientation of the metal-O-Si domains

[31]. Hence, the resulted amorphous patterns of the tested metal silicates could be a

result of the predominance of metal-O-Si bonds, rather than phase separated metal

oxide/SiO2 mixtures [32].

CHAPTER TWO


Figure 2.3 X-ray powder diffraction results for Al, Mg, Ca-silicate precipitates.

This difference was crucial for the proper choice of amorphous metal silicates instead

of the natural crystalline silicates with regard to the mechanical strength of the

complex compacts. In this perspective, naturally occurring metal silicates, specifically

phyllosilicates, are generally brittle and of weak binding capacity. Alternatively, they

would represent improper candidates when used as pharmaceutical fillers in solid

dosage forms. Such weakness could be theoretically attributed to the crystalline lattice

structure of metal silicates as they are composed of stacks of individual silicate layers

held together by weak van der Waals forces resulting in gap spacing between the

layers [33, 34]. On the other hand, chitin (Figure 2.4) displayed six broad peaks at

9.4, 12.9, 19.3, 23.5, 26.9 and 39.8, which are likely caused by polycrystalline

domains or disturbed crystal structure [35]. Such domains originate from the anti-

parallel arrangement of chitin molecules in the form which is stabilized by a high

number of hydrogen bonds formed within and between the molecules [36]

CHAPTER TWO


Figure 2.4 X-ray powder diffraction spectra for chitin-metal (Al, Mg, Ca) silicate

co-precipitates, chitin Mg silicate physical mixture, and chitin.

Co-precipitation of the metal silicates onto the chitin particles did not alter the

position of the amorphous domains of both chitin and metal silicates, as shown in

Figure 2.4. However, there was a decrease in the peak intensities of chitin in all the

chitin-metal silicates diffraction patterns when compared to that of chitin. This could

be attributed to dilution effect caused by the content of metal silicates in the complex.

Similarly, the x-ray diffraction patterns of chitin and magnesium silicate (taken as an

example for demonstration) physical mixtures prepared using a magnesium silicate

content of 32% (wt/wt) showed no alteration in the amorphous domain positions. In

addition, there were no noticeable differences with regard to the x-ray diffraction

patterns between the co precipitate and the physical mixtures in the case of chitin-Mg

silicate. This further demonstrates the physical association between chitin and metal

silicates.

CHAPTER TWO


The chitin–metal co-precipitate was screened, after drying and sieving the powder, by

SEM and compared with the original chitin powder, as shown in Figure 2.5. Chitin,

Figure 2.5.A, had changed its native structure from thin smooth, flat surface structure,

with folded edges, to three-dimensional compacts with the metal silicate co

precipitate, Figure 2.5.B for chitin-Mg silicate. Figure 2.5.C shows a larger view of

chitin-Mg silicate indicating the presence of inter-particulate voids and channels.

(A)

(B)

(C)

Figure 2.5 SEM of chitin (A), chitin-Mg silicate co-precipitate (B) and (C).

CHAPTER TWO


The disintegration mechanism of chitin-metal silicates was investigated by examining

the water uptake driving force of the powder. This was achieved by performing water

penetration rate and water infiltration experiments for chitin-Mg silicate as a

demonstrating example of chitin-metal silicate co precipitate.

Water penetration rate of chitin-Mg silicate at different particle size was carried out

and compared with Avicel® 200 at the same particle size (Figure 2.6). The choice of

using Avicel® 200 was based upon its free allowance to water passage without any

hindrance caused by gelling. Water penetration rate increased from 20 to 30 mL/min

with decreasing the particle size from 1400 m to 125 m of chitin-Mg silicate,

whereas the water penetration rate of Avicel® 200 increased from 7 mL/min to

18 mL/min with increasing the particle size from 125 m to 1400 m. Generally,

increasing a powder particle size allows larger voids between particles, thus higher

penetration rates as in the case of Avicel® 200. This case was the opposite for chitin-

Mg silicate. It seems that the voids between the particles have a little significance to

increase the passage of water amongst them. In spite of its high water penetration rate,

Figure 2.6 demonstrates that chitin-Mg silicate was found to be slightly hygroscopic.

Polymers with a higher moisture uptake capacity will be expected to be more prone to

accelerate tablet disintegration.

CHAPTER TWO


-2

0

2

4

6

8

10

12

25 35 45 55 65 75 85 95

0

5

10

15

20

25

30

35

40

125 300 710 1400

% G

ain

in

weig

ht

(w/w

)

% HumidityP

en

etr

ati

on

rate

of

wate

r, m

L/m

in

Particle size, μm Chitin-Mg silicate, water penetration rate

Avicel 200, water penetration rate

Chitin-Mg silicate, hygroscopicity

Figure 2.6 Water penetration rate of chitin-Mg silicate and Avicel® 200 as a

function of particle size (primary axis). Hygroscopicity of chitin-Mg

silicate co-precipitate performed using standard salt solutions of different

humidity conditions stored inside desiccators at room temperature for 1

week (secondary axis). Error bars presented as ± RSD.

The hygroscopicity measured for chitin-Mg silicate (Figure 2.6) clearly indicated that

chitin-Mg silicate only gained maximum moisture content up to 9.4% of its initial

weight at the 98% humidity condition. Water infiltration through capillary rise

experiment gave a clearer explanation to such behaviour when chitin-Mg silicate,

chitin, Mg silicate, and Avicel®

200 were allowed to come in contact with water from

the bottom side across a glass wool pledget. Capillary action seemed to have a major

contribution to the water uptake of chitin-Mg silicate (a measured rate of 0.145

mL/min) and almost similar to chitin (a measured rate of 0.15 mL/min). This indicates

that the capillary action is mainly contributed to chitin as the rate was measured to be

0.015 mL/min for Mg silicate. Avicel® 200, which showed a significant water

penetration (Figure 2.6), had no significant capillary action which was almost similar

to Mg silicate. This may suggest that decreasing the particle size of chitin-Mg silicate

CHAPTER TWO


(Figure 2.6) may have increased the water uptake through capillary action. As the

particle size was decreased more intra particulate voids may have come into contact

with each other giving rise to more capillary channels (see Figure 2.5.C for

illustration) for water to penetrate.

This investigation was further illustrated when studying tablets hardness versus

compression force for varying powder particle sizes; 125 m, 425 m, 1400 m

(Figure 2.7). Generally, a reduction in particle size is associated with an increase in

tablet mechanical strength. This increase is attributed to an increase in the surface area

available for inter-particulate attractions, as the particles become smaller [37].

However, when chitin-Mg silicate was used, it was found that varying the particle size

had no effect in increasing the mechanical strength of the tablets produced. Generally,

for materials with a fragmentation tendency, such as dibasic calcium phosphate

dihydrate and saccharose, the mechanical strength of the tablet seems to be almost

independent on particle size [38]. This could be the case for the chitin-metal silicate

particles which undergo fragmentation, as will be illustrated later, at early

compression stages which normally lead to a limited effect on tablet tensile strength

when varying the particle size.

CHAPTER TWO


0

5

10

15

20

25

30

35

40

45

50

0

50

100

150

200

250

30 35 40 45 50

Dis

inte

gra

tion tim

e, s

Hard

ness, N

Compression force applied, kN

Hardness, 1400 μm particle size (PS)

Hardness, 425 μm PS

Hardness, 125 μm PS

Disintegration time, s

Figure 2.7 Hardness and disintegration time as a function of compression force

for different particle size of chitin-Mg silicate co-precipitate. Tablets

were 12 mm in diameter and 400 mg weight.

With respect to tablets disintegration, chitin-Mg silicate, as shown in Figure 2.7,

showed a unique and distinctive characteristic whereby disintegration was

independent upon particle size and tablet hardness. Chitin-Mg silicate tablets,

produced from initial powder particle sizes of 125 m, 425 m, and 1400 m at

compression forces between 30-50 KN for each particle size, showed a superior

disintegration time, i.e. no longer than 5 seconds. This was achieved for tablet

hardness values ranging from 40-220 N. Once more, this may suggest that capillary

action was the dominant mechanism for disintegration irrespective of tablets tensile

strength. Therefore, the inter-particulate voids, as previously mentioned, would have

remained intact and unchanged through varying the powder particle size and the

compression force.

Processing chitin with metal silicates was found to cause alterations to chitin’s

powder compressibility and compactability. Regarding powder compactability, metal

CHAPTER TWO


silicates within the chitin-metal silicate complex have demonstrated an effective mean

to establish hard tablets while maintaining super-disintegration power, as could be

deduced from Figure 2.7. In the absence of metal silicates, chitin showed a maximum

tablet hardness of 73 N at a compression force of 50 KN. Increasing the content of

metal silicates resulted in an increase in tablet hardness (at the same compression

force) which followed the pattern shown in Figure 2.8 for Al, Mg, and Ca silicate-

chitin compacts. All types of chitin-metal silicates tablets showed a sharp increase in

the compaction properties (tablets hardness >140 N) while maintaining a low

disintegration time (<10 seconds) when the metal silicate content was increased up to

30% (wt/wt). Above this value, the increase in tablet hardness values became slower

whereas disintegration time increased sharply to values greater than 7 minutes for all

the chitin-metal silicates compacts. Pure metal silicates (100% metal silicate content

in Figure 2.8) showed good compaction properties but disintegration was slow (about

10 minutes for all chitin-metal silicates). This behaviour could, in a way, justify the

hypothesis that the optimum metal silicate content in chitin-metal silicates should not

exceed 30% (wt/wt) in order to maintain good compaction and super disintegration

characteristics. Figure 2.8 further indicates that the tensile strength of chitin-metal

silicates compacts was dependant upon the type of metal cation. The increasing

hardness of compacts was as follows: chitin-Al silicate > chitin-Mg silicate > chitin-

Ca silicate.

CHAPTER TWO


0

100

200

300

400

500

600

700

0

50

100

150

200

250

300

350

0 20 40 60 80 100

Dis

inte

gra

tio

n tim

e (

DT

), s

eco

nd

s

Hard

ness, N

% w/w metal silicate

Chitin-Al silicate

Chitin-Mg silicate

Chitin-Ca silicate

Chitin-Al silicate

Chitin-Mg silicate

Chitin-Ca silicate

Hardness

DT

Figure 2.8 Hardness and disintegration time as a function of chitin-metal (Al,

Mg, and Ca) silicate content. Tablets were 12 mm in diameter and

400 mg weight.

The trend of increase in compacts mechanical strength is mainly attributed to the

compacts porosity. Generally, tablets of low porosity will have a high mechanical

strength [39]. The incorporation of metal silicates onto the chitin particles through the

co precipitation process has established some modifications to the physical properties

of the chitin powder. This will be clearly demonstrated by powder compressibility

analysis of various chitin-metal silicates. Early investigation of the Heckel plots

indicated non-log-linearity of compression data. Therefore, Heckel analysis was not

adopted in this work as it may result in misinterpretation to the estimated intercept

and slope parameters. Therefore, the Kawakita analysis was adopted instead in order

to linearize the compression data.

CHAPTER TWO


Figures 2.9 and 2.10 show representative Kawakita plots for chitin-Mg silicate at

different concentrations of Mg silicate and for the three investigated types of metal

silicates in the chitin-metal silicates powders.

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

P/C

Pressure, MPa

32% Mg silicate

24% Mg silicate

19% Mg silicate

13% Mg silicate

Chitin

Figure 2.9 Kawakita plots for different concentrations of Mg silicate in the

chitin-Mg silicate co precipitate. Tablets were 12 mm in diameter and

400 mg weight.

CHAPTER TWO


0

20

40

60

80

100

120

0 10 20 30 40 50 60

P/C

Pressure, MPa

Chitin-Ca silicate

Chitin-Mg silicate

Chitin-Al silicate

Figure 2.10 Kawakita plots for chitin-metal (Al, Mg, Ca) silicate co precipitates.

Tablets were 12 mm in diameter and 400 mg in weight.

From the the data in the plots, the Kawakita constants a and 1/b are listed in Table

2.2. In terms of a constant, chitin showed the highest compressibility (highest a

value). Increasing the Mg silicate content from 13% to 32% (%wt/wt) lowered the a

value and therefore compressibility was decreased. In terms of metal type, chitin-Al

silicate had the highest compressibility followed by chitin-Mg silicate which in turn

was higher than chitin-Ca silicate.

Values of 1/b, which are an inverse measure of the amount of plastic deformation

occurring during the compression process increased with increasing the Mg silicate

content. This implies that increasing the Mg silicate content exhibited a lower degree

of total plastic deformation during the compression process. Hence, it would appear

that chitin exhibited a faster onset of plastic deformation during compression. On the

other hand, chitin-Al silicate had a higher degree of plastic deformation than chitin-

Mg silicate whereas chitin-Ca silicate showed the lowest degree. The product ab,

CHAPTER TWO


which is a measure of the extent of particle rearrangement, is shown in Table 2.2.

Table 2.2 Kawakita parameters for different concentrations of Mg silicate

precipitates in the chitin-Mg silicate co precipitate and for chitin-metal

(Al, Mg, Ca) silicate co precipitates.

Material Metal silicate

(% wt/wt)

Kawakita Parameters

a 1/b ab

Chitin 0 0.82 10.60 0.077

Chitin-Mg silicate 13 0.80 11.86 0.067




Chitin-Al silicate 32 0.78 14.82 0.052

Chitin-Ca silicate 32 0.70 23.89 0.029

It appears that the degree of particle rearrangement of chitin decreased with increasing

the Mg silicate content. This may imply that the metal silicate precipitated onto the

chitin particles may have reduced the surface micro-irregularities of chitin and

facilitated particle rearrangement during the densification phase of compaction. On

the other hand, chitin-Ca silicate showed the lowest degree of rearrangement (Table

2.2). It appears that chitin-Ca silicate had the highest degree of packing. Such a trend

could be correlated to the fact that chitin-Ca silicate had the highest true density

(1.766) of all the examined chitin-metal silicates.

Finally, the good compaction characteristics provided by chitin-metal silicates was

tested for their binding capabilities, disintegration time, and drug dissolution over

poorly compressible drugs such as paracetamol and metformin HCl as examples of

hydrophilic drugs and mefenamic acid as an example of a hydrophobic drug. Direct

compression and wet granulation processing formulations were tested for the

hydrophilic drugs. In addition, the performance of formulas containing paracetamol

and metformin HCl drugs directly compressed with Ca silicate was tested (see Table

2.1). Results are summarized in Table 2.3.

CHAPTER TWO


Table 2.3 Hardness, disintegration, and dissolution results for the paracetamol, metformin

HCl, and mefenamic acid tablets formulations.

Formula * Hardness (N) Disintegration Time (Sec) Dissolution (% Drug

Release at times 10, 20 min)

F1 103 44 91, 100

F2 118 48 86, 100

F3 144 261 67, 86

F4 98 41 94, 100

F5 112 50 90, 100

F6 159 336 75, 96

F7 126 84 60, 90

F8 131 300 42, 71

* See Table 2.1.

The dilution capacities (percentage of incompressible material) of paracetamol and

metformin HCl were 58.1% (wt/wt) and 56.8% (wt/wt), respectively, for direct

compression and wet granulation formulas containing chitin-Mg silicate as the

investigated binder. Hardness values for F1, F2, F4, and F5 (see Table 2.4) indicated

high binding capabilities with less than a minute of disintegration time for all the

formulas. Full drug release (% assay measured) was attained at the 20 minute

dissolution of both drug formulas. When Ca silicate was included in the paracetamol

and metformin HCl formulas (same drug dilution capacities as F1 and F4) as a filler

in direct compression mode (see F3 and F6 in Table 2.4), tablets displayed higher

hardness values with much higher disintegration time. This may indicate that metal

silicates functionality as disintegration promoters necessitated the presence of other

superdisintegrants (chitin in this case) to enhance tablet disintegration.

The performance of chitin-metal silicates was evaluated in formulations with

mefenamic acid as a model hydrophobic drug. Mefenamic acid was reported to be

soluble in alkali hydroxides [40]. Direct compression of mefenamic acid with chitin-

Mg silicate at the dilution capacity of 51.7% (wt/wt) resulted in hard tablets and 90%

drug release within 20 minutes of dissolution. In comparison with PonstanTM Forte

CHAPTER TWO


500 mg, as the commercial drug reference, percentage drug release at the 20 minutes

dissolution was much lower (71%). Therefore, the use of chitin-Mg silicate of alkaline

nature (pH 8.5 for 5% w/v aqueous dispersion) could improve the solubility of

mefenamic acid while maintaining intact physical properties of the tablets produced.

For example, disintegration time of the mefenamic acid formula, F7, was even lower

than PonstanTM Forte (F8) in which it was reported to compose of lactose, maize

starch, sodium lauryl sulphate, and pregelatinized starch as fillers, binders, and

disintegrants in addition to croscarmellose as the superdisintegrant [41]. Formula F7

was composed of one excipient, in addition to mefenamic acid and the lubricant,

which enhanced better binding, disintegration, and dissolution properties to the tablets

produced

2.4 Conclusions

Co-precipitation of a metal silicate on chitin particles offers industrial potential for

use as a single filler which has binding as well as super-disintegration properties and

can be used in directly compressed tablets or in wet granulation methodologies. The

co-precipitation process causes physical adsorption of the metal silicates onto chitin

particles as illustrated by the SEM data without any chemical interaction as evidenced

by the IR and XRPD analysis. The good disintegration property of the highly non-

hygroscopic product is most likely to be related to capillary action. Disintegration and

binding properties were found to be independent of particle size and compression

force applied. The final pH of the complex, the mechanical strength of the tablets

produced, and the powder compressibility and plasticity were all found to be

dependent on the identity of the metal silicate. Pharmaceutical applications using

formulations containing paracetamol, metformin HCl, and mefenamic acid indicated

the good binding and disintegration abilities of chitin–metal silicates with poorly

compressible and/or non-polar drugs.

CHAPTER TWO


2.5 References

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[3] Ritthidej GC, Chomto P, Pummangura S, Menasveta P. 1994. Chitin and chitosan

as disintegrants in paracetamol tablets. Drug Dev Ind Pharm 20:2109–2134.

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[5] Sabnis SS. 1996. Development of modified chitosans as excipients for use in drug

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[29] Coates J. 2000. Interpretation of infrared spectra. A practical approach. In:

Meyers RA, editor. Encyclopedia of analytical chemistry. Chichester: John Wiley &

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[30] Chen JJ, Thomas JJ, Taylor HFW, Jennings HM. 2004. Solubility and structure

of calcium silicate hydrate. Cement Concrete Res 34:1499–1519.

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Chystallography’’ for determining the symmetry and the structural type of new crystal

phases using Ba3MnSi2O8 as an example. J Univ Chem Tech Metall 42:363–368.

[32] Chambers JJ, Busch BW, Schulte WH, Gustafsson T, Garfunkel E, Wang S,

Maher DM, Klein TM, Parsons GN. 2001. Effect of surface pretreatments on interface

structure during formation of ultrathin yttrium silicate dielectric films on silicon. Appl

Surf Sci 181:78–93.

[33] Bolhuis GK, Holzer AW. 1996. Lubricant sensitivity. In: Alderborn G, Nistrom

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Dekker, Inc. pp. 517–560.

CHAPTER TWO


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Leatherhead, UK: Datapharm Communications Ltd.

CHAPTER THREE


3. CHARACTERIZATION OF THE IMPACT OF MAGNESIUM

STEARATE LUBRICATION ON THE TABLETING PROPERTIES OF

CHITIN-MG SILICATE AS A SUPERDISINTEGRATING BINDER WHEN

COMPARED TO AVICEL® 200

3.1 Introduction

Solid dosage forms, e.g. tablets and capsules, are the most popular and preferred drug

delivery systems. Tablet dosage forms are mainly composed of the API/APIs (active

pharmaceutical ingredient) and excipients [1]. Excipients include diluents, binders,

disintegrants, glidants and lubricants; the latter i.e. lubricants are usually added in the

final stages of mixing of the formulation components prior to compression. The main

function of lubricants is to prevent adhesion of compacts to the surface of the punches

and dies, used in pharmaceutical manufacture, thus facilitating their ejection from the

die cavity [2]. Furthermore, the presence of lubricants in formulated powder mixtures

reduces inter-particulate friction leading to improved flow properties [3]. Such effects

are mainly attributed to the ability of lubricants to be distributed as a surface film on

the base/carrier material [2]. Magnesium stearate (MgSt) is the most widely used

lubricant in pharmaceutical formulations [4]; the amount used is assessed during the

early stages of pharmaceutical formulation development, and does not usually exceed

2% of the total powder weight used in tablet manufacturing [5]. In the case of MgSt

the surface area per unit mass of powder mixture can be as high as 20% (w/w),

depending on the other ingredients present in the pharmaceutical formulation [6]. In

spite of the importance of lubricants in solid dosage forms, problems can occur when

lubricants are added to excipient/API mixtures. The compaction and/or disintegration

time of binders, fillers, and disintegrants has been reported to be negatively affected

by the presence of lubricants [7]. The possible deleterious effects of MgSt have been

attributed to the formation of a hydrophobic lubricant film on the surface of

formulation component particles resulting, effectively, in a physical barrier [8].

Hence, the binding properties of the particles are altered and the wettability of the

tablet ingredient particles will be negatively affected. This can result in retardation of

water penetration into tablets and thereby cause delayed dissolution of the API, as the

pore surfaces in the tablets become more hydrophobic [9, 10]. A decrease in crushing

CHAPTER THREE


strength is manifested in compacts made from microcrystalline cellulose (Avicel®

200) when concentrations of MgSt exceeding 2% (w/w) are used [11]. In addition, the

physico-chemical effects of MgSt are dependent on the mixing time of the lubricant

with the formulation components due to the redistribution of the lubricant on the

mixture of particles [10]. Use of pregelatinized starch (Starch® 1500), calcium

sulphate dihydrate, and amylase resulted in a large decrease in crushing strength,

accompanied by an increase in mixing time with the lubricant [12]. The extent of

lubricant sensitivity is dependent on a large number of factors, such as the nature and

physico-chemical properties of the lubricant and other tablet ingredients. Therefore, in

order to limit lubricant sensitivity, these factors must be considered in determining the

optimal level of lubricant(s) in a formulation. In this regard, minimal effect of

lubricant on powder compaction was reported for dicalcium phosphate dihydrate

particles due to the very irregular surface of the excipient preventing the formation of

a continuous film on blending with MgSt [13]. Moreover, low lubricant sensitivity is

displayed by materials (for example brittle materials such as dicalcium phosphate

dihydrate and β-lactose) which undergo high levels of fragmentation upon powder

compression [14]. In addition, the presence of other formulation components can

influence the film formation properties of lubricants and thereby minimize the

deleterious effects of the lubricant. For example, mixing of excipient particles with

MgSt and colloidal silica (Aerosil 200) can significantly suppress the negative effect

of the lubricant on the interaction between lubricated particles [15].

Processing of chitin with silica products offers significant advantages for the

exploitation of multifunctional excipients in the pharmaceutical industry. For

example, chitin-metal silicate co-precipitates have, recently, been reported to be

useful excipients, with appropriate binding and disintegration characteristics, when

compared to conventional super-disintegrants and fillers [16, 17, 18]. However, the

impact of chitin-metal silicate lubrication with MgSt has not been reported, especially

in cases where MgSt causes undesirable changes in tablet properties (as described

above). In the current investigation, the compaction and disintegration properties of

chitin-metal silicates at different concentrations of MgSt are reported. Comparison

with lubricated and unlubricated microcrystalline cellulose and its co-precipitated

form with magnesium silicate are also examined. In addition, the effect of MgSt on

CHAPTER THREE


the ejection force of chitin-Mg silicate and on the dissolution profiles of ibuprofen

and gemfibrozil (as model drugs exhibiting poor compactability/water solubility)

formulated with chitin-Mg silicate are evaluated.

3.2 Experimental

3.2.1 Materials

Chitin (measured 50th

percentile diameter d(0.5) = 216 µm, JBICHEM, Shanghai,

China), Avicel® 200 (measured d(0.5) = 201 µm, FMC BioPolymer, Philadelphia,

PA, USA), calcium hydrogen orthophosphate CaHPO4 (CHO) (measured d(0.5) = 203

µm after being passed through a 250 µm mesh sieve and collected on a 200 µm mesh

sieve, BDH Laboratory Supplies, Poole, UK), Na2SiO3.5H2O (BDH, Poole, UK),

MgCl2.6H2O (SIGMA Chemical Co, St. Louis, MO, USA), MgSt (d(0.5) = 3.1 µm,

Mallinckrodt Corporation, Raleigh, NC, USA), ibuprofen powder (d(0.5) = 82.5 µm,

Sigma, St. Louis, MO, USA), gemfibrozil powder (of a wide particle size distribution

from 40 to 300 µm with a d(0.5) = 110 µm, Zhejiang Excel Pharmaceutical Co., Ltd.,

Zhejiang, China), and Lopid 600 mg gemfibrozil tablets (batch number: 0212027,

expiry date: 01/2010, manufactured by Goedecke AG, Freiburg, Germany under

license from Parke-Davis, Pontypool, Gwent, U.K) were used. All reagents used were

of analytical grade.

3.2.2. Methods

3.2.2.1 Preparation of chitin-magnesium silicate and Avicel-magnesium silicate

powders

Into a solution containing 10.0 g of Na2SiO3.5H2O (dissolved in 400 mL of deionized

water), 10 g of chitin or Avicel® 200 were suspended under stirred conditions. 9.6 g

of MgCl2.6H2O was added to stoichiometrically react with sodium silicate to produce

suspended particles of the magnesium silicate, which co-precipitated onto chitin or

Avicel® 200. The particles were filtered using 20-25 m filter papers (ALBET 135,

Quantitative, Barcelona, Spain) then washed with deionized water until the filtrate

conductivity, measured using a conductivity meter (METTLER TOLEDO MPC227,

Greifensee, Switzerland), was less than 20 S. The product was dried in an oven at

CHAPTER THREE


90ºC for 3 h, passed through a 250 µm mesh sieve, collected on a 200 µm mesh sieve

and kept for further testing and characterization. If it is assumed that 1 mol of

Na2SiO3.5H2O reacts, stoichiometrically, with 1 mol of MgCl2.6H2O to produce

1 mol of MgSiO3, the final magnesium silicate mass content is calculated to be 32%

(w/w).

3.2.2.2. Tablet compression, crushing strength and disintegration testing

100.0 g of six powder blends of chitin-Mg silicate or Avicel® 200 or CaHPO4 or

Avicel-Mg silicate physically mixed with MgSt at concentrations of 0.25, 0.5, 1.0, 2,

5, and 10% (w/w) were prepared. Mixing was performed manually in a 2L Mini-blend

v-blender (GlobePharma, New Brunswick, NJ, USA). The v-blender was operated at

30 rpm for a period of 5 min. Each of the powder samples was subjected to

compression using a single 12 mm circular punch tableting machine (Manesty,

Merseyside, UK) at compression pressures of 156, 182, 208, 234 MPa. Tablet weight

was fixed at 400 mg. The crushing strength of the compacts was used to study the

compactibility of the manufactured tablets. By measuring crushing strength, it is

possible to compare results obtained for tablets formulated with different

ingredients/compositions or under different compaction pressures. Crushing strength

was calculated using the measured maximum force, F (N), which was applied

diametrically to fracture the tablet, using a hardness tester (Copley, Nottm Ltd,

Therwil, Switzerland). The crushing strength, σ, was calculated using the following

equation [19]:

σ =dL

F

2 (1)

where d (m) is the tablet diameter and L is the tablet thickness (m). The average

crushing strength of 10 tablets was recorded for each sample. Using the tablet

hardness measurement equipment, tablets were subjected to a diametrical

compression test after they had been allowed to remain at room temperature for 24 h

in a desiccator. Disintegration times were measured for chitin-Mg silicate, Avicel®

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200, and Avicel-Mg silicate tablets produced using a disintegration tester (Caleva,

Dorset, UK) in accordance with the USP 31 disintegration procedures for uncoated

tablets. Comparison of disintegration times between different materials was carried

out for tablets (12 mm diameter) compressed to reach a fixed crushing strength value

of 0.6 MPa (equivalent to the maximum crushing strength for Avicel® 200 at 10%

(w/w) MgSt concentration).

3.2.2.3. Compression data acquisition and analysis

Unlubricated and lubricated chitin-Mg silicate and Avicel® 200 samples, at MgSt

concentrations of 1 and 5% (w/w) for the lubricated samples, were separately

compressed by direct compression using a universal testing machine (UTM, RKM 50,

PR-F system, ABS Instruments Pvt., Ltd., Leipzig, Germany). The punch speed was

fixed at 10 mm/min. Different compression pressures from 10 to 70 MPa were

applied. Three tablets were prepared to ensure reproducibility. The tablets were flat,

12 mm in diameter and 400 mg in weight. Bulk density was determined using a

weighed 100 mL cylinder and a volumeter (Erweka GmbH, Heusenstamm, Germany).

20 g of the powder was gently filled into the cylinder. Bulk volume was read and bulk

density calculated, as the average of five measurements.

The powder compression behaviour of the samples was evaluated using Kawakita

analysis which was performed on three preparations of chitin-Mg silicate powder and

on three Avicel® 200 samples. All the tested samples were unlubricated and lubricated

(1 and 5% w/w) with MgSt. The Kawakita equation describes powder compression

using the degree of volume reduction, C [20]:

C = bP

abP

V

VV

10

0 (2)

Vo is initial volume and V is the volume of the powder column under an applied

pressure, P. The constant a is the minimum porosity of the material before

compression while the constant b relates to the plasticity of the material. The

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reciprocal of b defines the pressure required to reduce the powder bed volume by 50%

[21, 22]. Equation (2) can be rearranged in linear form as:

aba

P

C

P 1

(3)

Particle rearrangement can be affected simultaneously by the two Kawakita

parameters a and b. The combination of these into a single value, i.e. the product of

the Kawakita parameters a and b, may be used as an indicator of particle

rearrangement, and hence the powder packing density during compression. The

average P/C values and their relative standard deviation at compression pressures

between 10-70 MPa of the three tested un-lubricated and lubricated preparations and

samples were ascertained.

3.2.2.4. Particles sized distribution analysis

The particle size distribution of chitin, chitin-Mg silicate, Avicel® 200, and Avicel-

Mg silicate at MgSt concentrations of 0, 0.5, 1, and 5% (w/w), in the powder phase,

was measured (Malvern Mastersizer 2000; Malvern, Worcestershire, UK), using dry

powder, in the 0.02 µm to 2000 µm range. The instrument is equipped with a Scirocco

2000 unit as the dry powder feeder, with compressed air to transport the particles. The

optimum air pressure was set at 0.1 bar, which ensured no breakup of agglomerates;

the foregoing was verified by repeating the measurement five times for the same

sample collected at the end of each run. Moreover, reproducibility was tested for three

powder samples of chitin and Avicel 200 and for different preparations of chitin-Mg

silicate and Avicel-Mg silicate. Three diameter values were used to characterize the

particle population: d (0.1) 10th

, d (0.5) 50th

, and d (0.9) 90th

percentile diameter,

respectively. The average of fifteen particle size distribution measurements for each

powder and the percentage relative standard deviation for the d (0.9) were recorded.

3.2.2.5. Specific surface area

A gas sorption analyzer (Nova 2000, Quantachrome Co., Syosset, NY, USA) capable

of measuring surface areas from 0.01 to more than 2,000 m2/g was employed to obtain

nitrogen vapor adsorption isotherms at 77 K. Chitin, chitin-Mg silicate, Avicel® 200,

CHAPTER THREE


and Avicel-Mg silicate samples were heated to 60°C while being purged under a

stream of pure nitrogen. Purging was continued for 24 h prior to analysis and the

experiments were undertaken in duplicate.

3.2.2.6. Scanning electron microscopy

Chitin-Mg silicate and Avicel®

200 samples at MgSt concentrations of 0 and 5%

(w/w) were mounted on aluminum stubs and then coated with gold by sputtering at

1200 V and 20 mA for 105 sec using a vacuum coater. Samples were examined using

a FEI Quanta 200 3D SEM (FEI, Eindhoven, Netherlands)

3.2.2.7. Compression of chitin-Mg silicate using a high speed tablet press

The procedure used to prepare chitin-Mg silicate in section 2.2 was scaled up using

Na2SiO3.5H2O (2.5 kg), deionized water (100 L), chitin (2.5 kg), and MgCl2.6H2O

(2.4 kg). Stirring was carried out using a vertical mixer (Wuxi Mingzhou

Environment Protection Machinery & Equip Factory, Jiangsu, China) in a 100 L

stainless steel container The magnesium silicate suspension was filtered out using a

filter fabric (Varun Tex, Inc., Madhya Pradesh, India) fitted on top of a 100 L empty

container. Washing, drying, and sieving of the filter cake was carried out as described

in section 2.2. The preparation was repeated until 10 kg of chitin-Mg silicate were

produced. A 5 kg batch of the prepared chitin-Mg silicate was compressed using a

Fette P2100 rotary tablet press (Fette, Schwarzenbek, Germany) into which 43

circular punches (12 mm) were fitted. Compression was carried out without MgSt at

press speeds of 30,000, 50,000, 100,000, and 150,000 tablets / hr. A compression trial

with MgSt was carried out at a press speed of 150,000 tablets / hr. The ejection force

displayed on the instrument panel was recorded. Stickiness was visually observed on

the upper and lower punches. 60 tablets were randomly taken out, weighed, tested

using disintegration (10 tablets) and tensile strength (10 tablets) testers, and visually

observed for the appearance of any surface cracking.

3.2.2.8. Dissolution testing of ibuprofen and gemfibrozil tablets

The effect of MgSt on the dissolution profile of ibuprofen tablets composed of

400 mg ibuprofen and 300 mg of either of the following excipients: chitin-Mg silicate,

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Avicel® 200, and Avicel-Mg silicate was examined. The excipients were either

lubricated with 1 or 5% (w/w) MgSt, or unlubricated. Excipients were physically

mixed with ibuprofen and directly compressed into 13 mm circular tablets (700 mg

tablet mass) using a single punch tableting machine at a compression pressure of

182 MPa. Five tablets were used for each dissolution profile test. The dissolution

media was composed of phosphate buffer (pH 7.2). USP Apparatus II was used at a

paddle rotary speed of 50 rpm. For dissolution studies of gemfibrozil, the tablets were

composed of 600 mg gemfibrozil directly mixed with 224.5 mg of chitin-Mg silicate

and 25.5 mg of MgSt (3% w/w) followed by direct compression into 13 mm circular

tablets (850 mg tablet weight) using a single punch tableting machine at a

compression pressure of 182 MPa. Five tablets were used for each dissolution profile

test. The dissolution media was composed of a phosphate buffer (pH 7.5). USP

Apparatus II was used at a paddle rotary speed of 50 rpm.


3.3.1. Effect of magnesium stearate concentration on the crushing strength of

chitin and Avicel co-processed with magnesium silicate

The effects of the lubricant MgSt on powder compression for chitin-Mg silicate,

Avicel® 200, calcium hydrogen orthophosphate and Avicel-Mg silicate are shown in

Figure 3.1. The data show a general trend of decrease in tablet crushing strength as

the amount of MgSt added to powder blends increases. However for blends composed

of chitin-Mg silicate there is no significant change in crushing strength for MgSt

compositions up to 2% (w/w). We therefore see no evidence for a decrease in tablet

crushing strength when the MgSt concentration is increased up to 2% (w/w) for the

chitin-Mg silicate and MgSt blends (Figure 3.1). This contradicts the general notion

that tablet crushing strength decreases with increase in the MgSt concentration. For

example, it has been reported that for a cyclodextrin/calcium silicate/MgSt tablet

formulation, as the concentration of MgSt is increased above 1.5% (w/w), the

crushing strength of an optimized fast disintegrating tablet formulation decreases [23].

In addition to the concentrations of MgSt normally used, Figure 3.1 includes two

CHAPTER THREE


extreme concentrations, i.e. 5 and 10% (w/w) of MgSt. The aforementioned

concentrations of MgSt were included for the purpose of determining the extent of

any deleterious effect of MgSt on the compaction of chitin-Mg silicate powder. It is

clear, from the data in Figure 3.1 that the crushing strength of the compacts made of

chitin-Mg silicate decreases to almost half of the values recorded for the compacts

containing 0-2% (w/w) MgSt. Nevertheless, the addition of MgSt, up to 5 or 10%

(w/w), to chitin-Mg silicate powder still results in hard tablets with crushing strength

values reaching 2.0 MPa at a compression pressure of 234 MPa. Hence, chitin-Mg

silicate is able to accommodate up to 10% (w/w) of MgSt and still maintain intact

solid tablets.

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Figure 3.1 Effect of MgSt concentration on tablet crushing strength of chitin-Mg silicate, Avicel ®200, calcium hydrogen orthophosphate, and

Avicel-Mg silicate co-precipitates at different compression pressures. Tablets, 12 mm in diameter and weighing 400 mg each were used. A, B,

C, and D represent compression pressures of 156, 182, 208, 234 MPa, respectively.

CHAPTER THREE PUBLISHED ARTICLE (2)

N.H.M.Daraghmeh–PhD Thesis 114

The importance of this finding is clearly demonstrated when MgSt is added to separate

powders of Avicel® 200 and CaHPO4. The data in Figure 3.1 illustrate the fact that when

MgSt is added to microcrystalline cellulose or CaHPO4, the resultant tablet crushing

strength decreases. For example, in the case of MgSt concentrations of 0.25, 0.5, 1.0 and

5% (w/w), there was a 6, 48, 63, and 86% decrease, respectively, in tablet crushing

strength of Avicel® 200 compacts at a compression pressure of 182 MPa. However, the

percentage decrease in tablet crushing strength for lubricated CaHPO4 was 31, 29, 22,

and 16% for the 0.25, 0.5, 1.0 and 5% (w/w) MgSt concentrations, respectively, at a

compression pressure of 182 MPa. It is generally accepted that MgSt has a more negative

effect on the crushing strength of tablets constituted of deformable materials (e.g. Avicel®

200) than brittle ones (e.g. CaHPO4). Brittle materials are more likely to fracture and

fragment during compaction. As more fresh surfaces, not covered by lubricant particles,

are generated, they tend to bond together. Film formation on deformable particles, on the

other hand, weakens the bonding of the granules as there are less fresh surfaces formed

during compaction [14]. Therefore, the sensitivity of CaHPO4 to MgSt was less when

compared to Avicel® 200; especially at MgSt concentrations greater than 0.5% (w/w).

However, it is noted that the percentage decrease in tablet crushing strength for lubricated

CaHPO4 undergoes a significant decrease with increasing MgSt content. This behavior is

suggested to be a typical example of the combination of brittle (e.g. CaHPO4) and plastic

(e.g. MgSt) materials which plays a significant role in altering the physico-mechanical

characteristics of a material [24, 25]. Optimum tableting performance is generally

achieved by using such a combination which produces a synergistic effect; thus

improving functionalities such as compaction performance, flow properties, lubricant

sensitivity etc. Therefore, the small increase in tensile strength (detected mostly at the

10% (w/w) MgSt concentration for all working pressures in the data shown in Figure 3.1

and in particular for the mixtures compressed at 234 MPa) encountered with CaHPO4 as

the mass of MgSt was increased is, presumably, a result of a combination of CaHPO4 as a



brittle material, with magnesium stearate as a plastic material.

In performing the same powder compaction tests for lubricated Avicel® 200 on which

magnesium silicate was co-precipitated, powder sensitivity appeared to be insignificant.

This was evident from the lower decrease in tablet crushing strengths, up to MgSt

concentrations of 2% (w/w), when compared to Avicel® 200. Moreover, the data in

Figure 3.1 illustrates the finding that lubricated Avicel-Mg silicate maintains highly

compactable tablets at MgSt concentrations of 2 and 5% (w/w). Hence, the low lubricant

sensitivity of chitin-Mg silicate is likely to be due to the presence of Mg silicate co-

precipitated on chitin particles. Arguably, this behavior resembles the improved lubricant

sensitivity of coprocessed silicified microcrystalline cellulose (Prosolv®). Prosolv® is

microcrystalline cellulose containing 2% (w/w) colloidal silicon dioxide. Tablets

prepared with Prosolv have been reported to maintain crushing strength profiles when

MgSt (0.5% w/w) was added [26].

3.3.2. Effect of magnesium stearate concentration on the disintegration time of chitin

and Avicel co-processed with magnesium silicate

Comparison of the influence of composition on disintegration time between chitin-Mg

silicate, Avicel® 200, and Avicel-Mg silicate at the 0, 0.25, 0.5, 1.0, 2, 5, and 10 % (w/w)

MgSt (Figure 3.2) is only possible for tablets with the same crushing strength (in MPa).

Since the maximum possible crushing strength attained for lubricated Avicel® 200 was

recorded as 0.6 MPa, and since the disintegration time for chitin-Mg silicate is

independent of crushing strength [18], disintegration time testing was carried out up to

this value of crushing strength for all the tested materials. Although short disintegration

times are often associated with tablets with poor crushing strength, this crushing strength

range was used to in order to fairly examine the contribution of lubrication on the tablets’

disintegration time. The hydrophobic character of MgSt appears to have little effect on

chitin-Mg silicate powder; whereas in the case of Avicel®

200 the influence of the

lubricant on its disintegration time is, by comparison, distinctly noteworthy (Figure 3.2).

The super-disintegration power of chitin-Mg silicate is retained at a MgSt concentration

of 2% (w/w). Above this concentration, disintegration did not exceed a maximum time of

5 min at 10% (w/w) concentration of MgSt. Even though tablet crushing strength values



for Avicel® 200 decreased, due to the presence of MgSt, the disintegration time remained

high. The results for the 5 and 10% (w/w) concentrations of MgSt clearly demonstrate the

hydrophobic hindrance of the lubricant coat towards water penetration, as tablets

disintegrated within 17 and 30 min, respectively.

Figure 3.2 Effect of MgSt concentration on the disintegration time of chitin-Mg silicate,

Avicel® 200, and Avicel-Mg silicate tablets. Tablets were 12 mm in diameter and 400 mg

in weight, compressed to reach a fixed crushing strength value of 0.6 MPa.

On the other hand, the data shown in Figure 3.2 indicates that modification of Avicel®

200 with Mg silicate co-precipitate does not decrease the long disintegration time

encountered with lubricated Avicel® 200 when the former is also lubricated. The

aforementioned finding gives more credence to the use of chitin-magnesium silicate,

when disintegration time and drug dissolution are significant parameters in formulations.

The difference in disintegration time between tablets formulated with chitin-Mg silicate

or Avicel® 200 highlights the difference in particle-particle (MgSt-excipient) distribution

(as will be discussed below).



3.3.3. Compressibility analysis of chitin and Avicel co processed with magnesium

silicate

In order to attain an understanding of the effects of lubricant on powder compression, at

the particulate level, it was important to carry out Kawakita plot analysis (Table 3.1) of

the two plastically deforming materials chitin-Mg silicate (Figure 3.3) and Avicel® 200

(Figure 3.4).

Table 3.1 Kawakita parameters for lubricated (with MgSt) and unlubricated chitin-Mg

silicate and Avicel® 200.

Magnesium Stearate

(%,w/w) Slope Intercept a ab b 1/b

Chitin-Mg silicate

0 1.33 23.217 0.74 0.043 0.05757 17.37

1 1.34 9.6623 0.74 0.103 0.138963 7.19

5 1.35 8.5486 0.73 0.116 0.158669 6.30

Avicel® 200

0 1.49 11.899 0.66 0.084 0.125767 7.95

1 1.37 12.707 0.72 0.078 0.10798 9.26

5 1.40 18.592 0.71 0.0537 0.075307 13.27

The choice of the Kawakita plot is based on the fact that different densification changes

from the bulk density state to compressed state of powders, on the assumption of e.g. the

appearance of agglomerates, will directly influence the powder volume reduction upon

compression. For chitin-Mg silicate, the insignificant change in the value of the constant

a for the unlubricated chitin-Mg silicate, at MgSt concentrations of 1 and 5% (w/w),

indicates that chitin-Mg silicate shows no change in compressibility. Theoretically, the

constant, ‘a’ is the minimum porosity of a material before compression. Therefore, the

porosity of chitin-Mg silicate remains unchanged for the unlubricated powder and at the 1

and 5% (w/w) concentrations of MgSt.



Figure 3.3 Kawakita plots for unlubricated (0% w/w) and lubricated (1%, 5% w/w)

chitin-Mg silicate with MgSt. Tablets were 12 mm in diameter and 400 mg in weight.

Figure 3.4 Kawakita plots for unlubricated (0% w/w) and lubricated (1%, 5% w/w)

Avicel® 200 with MgSt. Tablets were 12 mm in diameter and 400 mg in weight.



The foregoing result can be accounted for by the lack of change in bulk density of chitin-

Mg silicate (illustrated in Table 3.2) and indicates that the initial particle size remains

unchanged for both lubricated and unlubricated chitin-Mg silicate.

Table 3.2 Physical parameters for unlubricated and lubricated chitin, chitin-Mg silicate,

Avicel® 200 and Avicel-Mg silicate powders.

Excipient

Magnesium

Stearate

(%, w/w)

Bulk density

(g/mL)

Particle size distribution (μm)

Specific surface

area

(m2/g), %RSD

d(0.1) d(0.5) d(0.9) % RSD

Chitin

0.0

0.5

1.0

5.0

0.17

0.17

0.17

0.18

70.7 216.6 418.6 0.46

72.5 217.5 416.4 0.37

71.3 217.9 413.5 0.51

60.6 218.9 414.6 0.38

48.80, 1.70

43.81, 1.29

37.94, 1.90

29.52, 1.08

Chitin-Mg

silicate

0.0

0.5

1.0

5.0

0.32

0.32

0.33

0.33

50.8 206.8 392.3 0.37

49.0 207.0 388.0 0.34

37.1 202.6 394.3 0.43

15.9 202.1 391.4 0.41

17.60, 1.48

22.60, 1.27

20.30, 1.41

20.90, 1.35

Avicel® 200

0.0

0.5

1.0

5.0

0.35

0.41

0.43

0.41

74.2 201.6 367.4 0.45

76.5 217.3 596.4 0.51

83.2 220.4 648.9 0.36

36.5 204.9 439.6 0.44

0.78, 3.20

0.53, 3.80

0.54, 3.31

0.58, 3.90

Avicel-Mg

silicate

0.0

0.5

1.0

5.0

0.41

0.41

0.41

0.41

74.1 201.0 383.2 0.41

60.7 206.9 394.7 0.39

45.6 209.2 397.0 0.48

32.8 212.3 406.3 0.38

21.20, 1.29

18.20, 1.76

18.32, 1.21

19.80, 1.13

On the other hand, Avicel® 200 exhibits an increase in the a value, i.e. a higher increase

in porosity, when MgSt is added at concentrations of 1 and 5% (w/w); thus highlighting

the increase in particle size when Avicel®

200 is subjected to lubrication. It should be

noted that the minimum porosity attained (maximum particle size before compression)



for Avicel® 200 was recorded for the powders in the order: lubricated Avicel

® 200 (1%

(w/w) MgSt> lubricated Avicel® 200 (5% (w/w) MgSt) > unlubricated Avicel

® 200 (this

trend in particle size will be examined further throughout the discussion).

Values for the product ab, which is a measure of the extent of particle rearrangement

during compression, are shown in Table 3.1. The degree of particle rearrangement of

chitin-Mg silicate increases with increasing MgSt content. Generally, particle

rearrangement is determined by the flow of smaller particles into the voids between larger

particles; therefore it would be expected that the presence of a lubricant would minimize

inter-particle friction and facilitate particle slippage. Apparently, from the elevation shift

(downward in this case) of the gradient of the data for the lubricated, when compared to

unlubricated, chitin-Mg silicate (Figure 3.3), at any fixed pressure value, the degree of

volume reduction (C) increases when MgSt is added to chitin-Mg silicate; allowing

improved consolidation behavior. This, presumbably, brings the particle surface areas

into closer proximity as new surface and denser compacts are formed. However, this was

not the case for Avicel® 200 which, when lubricated, produced a decreased level of

particle rearrangement as shown by the decreased ab values (Table 3.1) for the 1 and 5%

(w/w) MgSt concentrations. On the other hand, the elevation of the gradient of the data

for the 5% (w/w) lubricated Avicel® 200 is shifted (upward in this case) when compared

to unlubricated Avicel® 200 (Figure 3.4) indicating a decrease in volume reduction of the

Avicel, when lubricated to this extent. It is hypothesized, from the a and ab values, that

for Avicel® 200 the degree of particle-particle interaction increases when lubricated with

MgSt. The foregoing suggestion is in agreement with the data of Faqih et al., [27] who

reported an improvement in powder flow properties of microcrystalline cellulose due to

the presence of coarse particles of Avicel agglomerates when MgSt was present at a

concentration of 0.25% (w/w). In the case of chitin-Mg silicate, a similar effect of

lubricant was not observed.

Values of 1/b, which are an inverse measure of the amount of plastic deformation



occurring during the compression process, decrease with increasing MgSt content (Table

3.1) for chitin-Mg silicate (i.e. increase in plasticity). But, the plasticity of Avicel

decreases with increasing MgSt content (increasing 1/b values in Table 3.1). The

increased level of chitin-Mg silicate particle rearrangement, accompanied by its increased

level of plasticity upon lubrication, indicates an increased tendency for particle

fragmentation during compaction. The extent of particle fragmentation will have a

considerable influence on susceptibility to lubrication [28]. Generally, the bonding

properties of a highly fragmenting material seem not to be significantly affected upon

lubrication as clean, lubricant-free surfaces are created by fragmentation [14].

Nevertheless, lubricated Avicel® 200 (which showed a decreased level of particle

rearrangement and plasticity) may undergo a decreased number of surface contact points

between the compressed particles upon fragmentation. The extent of this decrease was

highly significant at 5% (w/w) MgSt concentration resulting in the lowest powder volume

reduction and the lowest tablet crushing strength values. Such behavior is the most likely

reason for the weakness of lubricated Avicel®

200 compacts compared to lubricated

chitin-Mg silicate. The aforementioned hypothesis is further supported by the b values in

Table 3.1. The constant b is inversely related to the yield strength of the particles and the

higher the value of b, the greater the total plastic deformation occurring during

compression [29]. Total plastic deformation creates more contact points for inter-particle

bonding [30]. Thus, higher b values indicate high tablet crushing strength. It is clear,

from the data presented in Table 3.1, that lubricated chitin-Mg silicate has higher b values

when compared with Avicel® 200.



3.3.4. Particle size distribution, bulk density, and specific surface area

measurements of unlubricated and lubricated chitin and Avicel co-processed with

magnesium silicate

Evidence for the lack of change in particle size of chitin-Mg silicate, when lubricated

with MgSt, is illustrated in Table 3.2. The measured d (0.5) and d (0.9) values for chitin-

Mg silicate particle size remain almost unchanged at MgSt concentrations of 0.5, 1, and

5% (w/w), respectively, when compared to unlubricated chitin-Mg silicate. The same

behavior occurs for the d (0.5) and d (0.9) values of lubricated and unlubricated chitin.

For Avicel®

200, there is an increase in the d (0.5) values at 0.5 and 1% (w/w) MgSt

concentrations; reaching a maximum of 220 µm (at the 1% (w/w) lubricant

concentration). In addition, at the same lubricant concentrations (0.5 and 1% w/w), the d

(0.9) values for lubricated Avicel® 200 indicate the presence of larger particles, reaching

a particle size of 649 µm (at 1% w/w lubricant concentration). This is evidence for the

presence of Avicel agglomerates at these concentrations of MgSt. However, at the 5%

(w/w) lubricant concentration, Avicel® 200 undergoes a decrease in the d(0.5) and d (0.9)

values (205 µm and 440 µm, respectively) when compared to Avicel® 200 lubricated

with MgSt at the 0.5 and 1% (w/w) concentrations (Table 3.2). Nevertheless,

agglomerates, albeit to a lesser extent when compared to the 0.5% lubricant concentration

sample, may still be present as indicated by the d(0.9) value of 440 µm. The differences

in particle size distribution are reflected in the measured bulk densities for the

unlubricated and lubricated chitin, chitin-Mg silicate and Avicel®

200 (Table 3.2). The

bulk densities of chitin and chitin-Mg silicate, when lubricated with MgSt, remain almost

unchanged; similar to the particle size distribution behavior. Whereas, Avicel® 200 shows

an increase in bulk density when lubricated with MgSt, thereby indicating the

contribution of the formed agglomerates to the increase in powder bulk density; as more

particles result in more mass occupying the same volume.

The effect of co-precipitated magnesium silicate on particle size distribution and bulk

density was examined for Avicel® 200. It is evident from the fixed bulk density and the

slight increase in the d (0.9) values for lubricated Avicel-Mg silicate compared to



lubricated Avicel®

200 (Table 3.2) that magnesium silicate minimizes the adhesion

potential of lubricated Avicel® 200. Therefore, the increase in particle size of Avicel

®

200 can be correlated to the cohesive tendency of MgSt to enhance particle

agglomeration [31]. The most probable mechanism, for lubricated Avicel® 200, starts by

partial filling of particle cavities, then quasi-total filling of cavities, and, finally, the

formation of a peripheral layer of varying composition around the particles [32]. The

particle size distribution results, Table 3.2, illustrating such agglomeration were measured

at a MgSt concentration of 1% (w/w) added to Avicel® 200. However, at higher

concentrations (in this case 5% w/w) of MgSt, the interaction favors de-agglomeration.

At the 5% (w/w) MgSt concentration, agglomerates reach a critical size where an

equilibrium occurs between breakdown and size increase of the agglomerates [32]. The

absence of an increase in particle size distribution for the lubricated chitin-Mg silicate, in

the presence of MgSt, indicates the absence of agglomeration. This conclusion is based

on the assumption that chitin-Mg silicate has a higher uptake capacity for MgSt inside its

cavities before forming the peripheral layer around the particles. Such an assumption is

based on the fact that chitin and its derivates (like chitosan) are well characterized by

their high absorption capacities for fatty acid materials (e.g. MgSt). In this context, it

should be noted that chitin does not necessarily need to be converted to chitosan in order

to absorb/adsorb fatty acids [33].

The decrease in the crushing strength values of lubricated Avicel® 200, the observed

agglomeration and lack of agglomeration for lubricated Avicel®

200 and chitin-Mg

silicate, respectively, are theoretically considered to be related to their interaction with

MgSt. This hypothesis is based upon the physical, chemical and geometric properties of

the particles. For example, the agglomeration of particles when lubricated with MgSt is

related to the electrostatic charging of particles during blending of dry powders [28, 34].

In this regard, it is suggested that the cohesive characteristics of MgSt may enable MgSt

auto-agglomerates to stick to oppositely charged particles and thus form larger



agglomerates of high MgSt content. In relation to the foregoing statement, the

physicochemical properties of the chitin surface are important. The surface of chitin has

been reported to possess a greater tendency for the adsorption of highly hydrophobic

materials compared to materials of low hydrophobicity. It has also been suggested that

the difference is likely to be due to partitioning of the compounds into the chitin particles

and not due to adsorption at the surface of the particles [33]. Therefore, the distribution of

MgSt on the surface of Avicel (as a peripheral layer) will not be the same as that on the

surface of chitin or chitin-Mg silicate; most probably because of their high adsorption or

partitioning tendencies towards MgSt. With regard to geometric structure, Ohta et al. [35]

suggested that the deleterious effect of MgSt on tablet hardness cannot be attributed to

the hydrophilic structure of silica particles but to the geometric structure which they

defined as a three-dimensional property such as porosity, particle size and specific

surface area. They concluded that the increase in tablet hardness of lubricated Avicel®

PH-101 with MgSt was due to the presence of hydrophilic porous silica of high surface

area. This explains the role of co-precipitated magnesium silicate onto chitin or Avicel

particles in minimizing the deleterious effect of MgSt on tablet hardness. Such an

assumption is based on the fact that synthetic magnesium silicate has a highly porous

structure [36]. Studies reported by Late et al. [23] lend support to this idea by

hypothesizing that the combined use of calcium silicate (Rxcipients FM 1000®) with

superdisintegrants, provides acceptable tablet hardness whilst concomitantly allowing

rapid tablet disintegration; in less than 30 seconds in the mouth. Furthermore, the co-

precipitated synthetic magnesium silicate has a high adsorption capacity for fatty acids

(MgSt in this case) [36, 37]. This is due to the presence of the negatively charged silanol

groups (≡Si−OH) as the most active groups on the surface; they normally provide the site

for physical adsorption of organic particles [38], more specifically those which carry a

positive electrostatic charge e.g. MgSt [39]. Hence, the lack of agglomeration of chitin-

Mg silicate could be correlated to the peripheral layer formation of MgSt in a different



manner than for Avicel®

200 particles. This is due to the fact that chitin and Mg silicate

have adsorption/absorption tendencies for MgSt. As stated earlier, MgSt can partition

inside chitin particles. In addition, the minimal extent of aggregation and decrease in

tablet crushing strength values for Avicel-Mg silicate particles accounts for the role of

magnesium silicate in hindering peripheral layer formation.

The extent of MgSt distribution onto particle surfaces can be correlated with their specific

surface areas, illustrated in Table 3.2, since surface coverage is related to the geometric

structure of the particles [35]. Chitin exhibits a high specific surface area (48.8 m2/g)

when compared to Avicel® 200 (0.78 m

2/g) in spite of a similar particle size (Table 3.2).

When chitin is lubricated with MgSt, the particles undergo a decrease in specific surface

area from that of unlubricated particles, but this parameter (for unlubricated and

lubricated chitin) remained significantly higher than that for unlubricated and lubricated

Avicel®

200 (Table 3.2). This suggests that chitin has a highly porous structure giving

rise to more surface area for MgSt distribution than is the case for Avicel® 200. Co-

precipitation of magnesium silicate onto chitin particles results in a decrease in the

specific surface area (17.6 m2/g) compared to chitin, but it still remains ~23 times higher

than Avicel® 200 (specific surface area of 0.78 m

2/g). Upon lubrication with MgSt (at

concentrations of 0.5% and 5.0% w/w), the specific surface area of Avicel® 200

decreases, as expected, due to the coverage of the micro-irregular surface by the added

lubricant. However, it would be hard to judge the extent of this decrease for different

lubricant concentrations as Avicel particle size varies at all concentrations of MgSt

(Table 3.2). In the case of chitin-Mg silicate, lubrication caused no significant alteration

in the high specific surface areas found for the chitin-Mg silicate particles (Table 3.2).

This finding further confirms the high uptake capacity of the particles towards coverage

with MgSt. Finally, co-precipitation of magnesium silicate on Avicel particles results in a

higher specific surface area (21.2 m2/g) when compared to Avicel

® 200 (0.78 m

2/g), as

illustrated in Table 3.2. Upon lubrication with MgSt, at 0.5 and 5.0% (w/w), the



measured specific surface area did not change significantly from that for unlubricated

Avicel-Mg silicate. This explains the lower reduction in crushing strength values of

lubricated Avicel-Mg silicate when compared to lubricated Avicel®

200 (Figure 3.1) as

the surface of Avicel-Mg silicate provides more contact area upon compression than

Avicel® 200.

In summary the high lubricant uptake capacity of chitin-Mg silicate, due to its high

surface area, displays minimal (if any) agglomeration as indicated by the particle size

distribution. This is confirmed by the lack of change in values of a but increased ab

values obtained from the Kawakita analysis. On the other hand, the relatively low surface

area of Avicel® 200 results in complete coverage with MgSt giving rise to an increased

level of agglomeration, as indicated by the increased a and decreased ab parameter values

from the Kawakita analysis. The change in particle size, therefore, contributes to the

change in particle behavior towards compression. Theoretically, the tensile strength of

agglomerates decreases with increase in particle size [40]. Therefore, the observed

decrease in the tablet crushing strength, for Avicel® 200 when lubricated with MgSt, can

be correlated to its tendency towards agglomeration.

3.3.5. Scanning electron microscopy of lubricated and unlubricated chitin and Avicel

co processed with magnesium silicate

Particle shape and size were examined using scanning electron microscopy (Figure 3.5).

When comparing the surface of chitin powder, Figure 3.5.A, with the surface of chitin-

Mg silicate, Figure 3.5.B, it is clear that chitin undergoes a change in topography from a

flat, smooth surface to a more irregular three dimensional compact. The addition of MgSt

did not change the visual appearance of chitin-Mg silicate particles when observed at the

same magnification level (Figure 3.5.C). However, for Avicel® 200 particles visually

observed at the magnification level of 400x (Figure 3.5.D) can only be clearly observed

at a lower magnification level of 200x (Figure 3.5.E). In other words, a reduced depth of

focus was used to visualize large particles (agglomerates). Therefore, the massive particle

of Avicel® 200 in Figure 3.5.D could be an agglomerate of more than one particle.



Figure 3.5 SEMs of un-lubricated chitin (A), un-lubricated chitin-Mg silicate (B),

lubricated particles of chitin-Mg silicate up to 5% (w/w) MgSt (C), un-lubricated Avicel®

200 (D), and lubricated Avicel® 200 up to 5% (w/w) MgSt (E).

3.3.6. Performance of chitin-Mg silicate on the high speed tablet press machine and

the role of MgSt

The performance of a batch of chitin-Mg silicate powder on the Fette high speed tableting

machine was tested. The output parameters are shown in Table 3.3. At all the Fette press

speeds, used in steps 1-4 in Table 3.3, no stickiness was observed on the lower and upper

surfaces of the punches. This is further quantitatively indicated by the constant weight of

the tablets. Tablet crushing strength and disintegration time remained relatively constant

at all press speeds. With respect to the ejection force values, these typically increased

with increasing press speed. Fortunately, they still remained below the maximum

acceptable limit of 300 N in tablet compression [41].



Table 3.3 Effect of Fette P2100 tablet press compression speed on unlubricated and

lubricated (up to 0.5% w/w with MgSt) ejection force for chitin-Mg silicate, stickiness to

the punches, tablet crushing strength, disintegration time, appearance of cracks and tablet

weight. Tablets were 12 mm circular.

Step Action Speed,

tablet/hr

Force

applied

(kN)

Ejection

Force,

(N)

Stickiness Tablet

crushing

strength,

(MPa)

Tablet

disintegration

time, (s)

Cracks Tablet

average

weight,

(mg)

1 - 30,000 9.9 140

No

sti

ckin

ess

1.5-2.1 12 Exist 640±2

2 Increase

Fette speed

50,000 8.1 182 1.5-2.0 12 Exist 640±3

3 Increase

Fette speed

100,000 9.6 242 1.2-1.5 12 Exist 640±4

4 Increase

Fette speed

150,000 9.6 278 1.5-1.8 12 Exist 640±5

5 With Mg

stearate,

0.5% (w/w)

150,000 10.7 53 1.5-2.1 12 None 640±3

However, the appearance of surface cracks was the major defect observed. Crack

formation is usually caused by the shear stress generated by die-wall friction during

ejection of the tablets [42]. To reduce die-wall friction, MgSt was applied (step 5 in Table

3.3) to the formula at a concentration of 0.5 % (w/w). It is clear from the data presented

in Table 3.3 that MgSt plays a significant role in reducing die-wall friction and thus

eliminating the development of cracks.

3.3.7. Dissolution of ibuprofen and gemfibrozil tablets formulated by direct

compression with chitin and Avicel co-processed with magnesium silicate

The extent of MgSt sensitivity was investigated in relation to the dissolution profile of

two model drugs: ibuprofen and gemfibrozil. In addition to their poor compressibility, the

two drugs were chosen because of the high cohesive characteristics of their bulk powders.

Therefore, they may require high concentrations of MgSt in order to overcome such

behavior [43]. However, this could negatively affect the crushing strength of the tablets.

In the case of ibuprofen using lubricated (1% and 5% w/w) and unlubricated chitin-Mg



silicate, Avicel® 200, and Avicel-Mg silicate results in the drug dissolution profiles

shown in Figure 3.6.

0

20

40

60

80

100

120

0 10 20 30 40 50

Dru

g r

ele

as

e (

%)

Time (min)

CMS, CMS+1% MgSt, and CMS +5%MgSt, > 2.27 MPa

AMS-1% MgSt, 1.91 MPa


Avicel-5%MgSt, 0.85 MPa




Figure 3.6 Dissolution profiles for ibuprofen (400 mg strength) tablets formulated with

unlubricated and lubricated (1% and 5%, w/w) chitin-Mg silicate (CMS), Avicel®, and

Avicel-Mg silicate (AMS) using physical mixing and direct compression. MgSt was used

as the lubricant. Tablets (700 mg) were 13 mm in diameter and compressed at 182 MPa.

Tablet crushing strength values are included in the legend for each specific powder.

It is clear from the data shown that ibuprofen tablets (400 mg strength) containing

lubricated and unlubricated chitin-Mg silicate exhibit full drug release within 5 min of

dissolution time. The measured tablet crushing strength remained almost unchanged for

the lubricated and unlubricated tablets (around 2.27 MPa). This finding indicates that the

fast drug release of ibuprofen tablets is unaffected by lubricated chitin-Mg silicate, which

maintains its super-disintegration and tensile strength powers when lubricated. Ibuprofen

tablets, with an average crushing strength value around 2.0 MPa, containing unlubricated

Avicel® 200 showed slow drug release (Figure 3.6). But, when Avicel

® 200 was

lubricated with 1 and 5% (w/w) MgSt the tablet crushing strength values decreased to



1.27 and 0.85 MPa, respectively. Thus faster dissolution profiles result, as expected, from

weak crushing strength tablets. When Avicel® 200 was replaced by Avicel-Mg silicate

co-precipitate, the tablet lubricant sensitivity towards decreased crushing strength values

was minimized, as the ibuprofen tablets retained a crushing strength of 1.93 MPa. This

was achieved for the 1 and 5% (w/w) concentrations of MgSt within the Avicel-Mg

silicate powder. With regard to drug dissolution, ibuprofen drug release was almost

unaffected when 1% (w/w) MgSt was used. However, when 5% (w/w) MgSt was used,

drug dissolution was found to be slower as the tablets maintained their high crushing

strength values, but with slower disintegration time (as indicated in Figure 3.2).

In the case of gemfibrozil (a lipophilic drug), the data in Figure 3.7 shows that

gemfibrozil (600 mg) tablets containing chitin-Mg silicate and 3% (w/w) of MgSt display

a similar dissolution profile to the Lopid tablets when the later is used as a reference.

According to the United States Patent 5726201, Lopid tables are composed of calcium

stearate and talc (both as lubricants) at the percentages of 1.9 and 2.8 (%w/w)

respectively. Therefore, the importance of such dissolution similarity finding lies in the

fact that in a formulation containing chitin-Mg silicate (as filler, binder, and disintegrant)

together with a water insoluble and highly hydrophobic active ingredient (gemfibrozil), a

high concentration of MgSt can be safely used to attain the desired dissolution profile.

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35

Dru

g r

ele

as

e (

%)

Time (min)

Gemfibrozil-Chitin-Mg silicate

Lopid

Figure 3.7 Dissolution profile of gemfibrozil (600 mg strength) tablets formulated with

chitin-Mg silicate by physical mixing and direct compression. The lubricant (MgSt)

concentration was 3% (w/w). Tablets (850 mg) were 13 mm in diameter and, compressed

at 182 MPa. Lopid tablets (600 mg strength and 850 mg weight) were used as a reference.



3.4 Conclusions

Magnesium silicate co-precipitated on chitin and Avicel provides advantageous

formulation processing, by minimizing the deleterious effects of MgSt. The addition of

MgSt as a lubrication aid did not show a significant variation in disintegration,

dissolution, and crushing strength of compacts made from chitin-Mg silicate. Such

variation was clearly observed when a comparison was made with Avicel®

200. This may

be attributed to the high surface area and porous structure of chitin and Mg silicate. In

this respect, co-precipitation with magnesium silicate changes Avicel® 200 into a less

lubricant sensitive excipient, whilst the disintegration time remains high. Unlike Avicel®

200, lubrication with MgSt shows improved powder consolidation behavior and powder

properties for chitin-Mg silicate with no effect on particle size distribution. MgSt proved

to be highly efficient in lowering the ejection force and eliminating the appearance of

surface cracks in chitin-Mg silicate tablets, at high compression speeds. A slight

deleterious effect of MgSt was evident when two hydrophobic drugs were prepared in

compacts made from chitin-Mg silicate.

Despite the fact that the studies reported in this chapter have shown that chitin-metal

silicates can be used as efficient multifunctional excipients, it is important to note that

some active pharmaceutical ingredients (APIs) are chemically incompatible with metal

ions [44-46]. Therefore, in order to be able to use such APIs another multifunctional

excipient based on mannitol, which is a common tablet excipient, and chitin is proposed

and has been investigated. The results of such studies are reported in Chapters 4 and 5 of

this thesis.



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CHAPTER FOUR


4. PREPARATION AND CHARACTERIZATION OF A NOVEL

CO-PROCESSED EXCIPIENT OF CHITIN AND CRYSTALLINE

MANNITOL

4.1 Introduction

In the pharmaceutical industry, solid dosage formulations require different types of

excipients to be added to the active pharmaceutical ingredient(s) in order to facilitate

manufacturing and to achieve the required physicochemical properties (e.g. flowability,

compressibility, disintegration, dissolution, stability, etc.). Excipients are incorporated in

formulations using different techniques such as direct compression, wet or dry

granulation as well as spray or freeze drying [1].

Single-component excipients do not always provide the requisite

performance/physicochemical properties to allow certain active pharmaceutical

ingredients to be formulated or manufactured adequately. As a result, drug formulation

scientists have relied on excipients used in combination and often introduced

commercially by excipient manufacturers. Such combinations fall into two broad

categories: physical mixtures and co-processed excipients. Co-processed excipients are

combinations of two or more excipients that possess performance advantages that cannot

be achieved using a physical admixture of the same combination of excipients [2]. The

use of different co-processed excipients has been investigated to overcome deficiencies

arising from single-component excipients and existing formulations [3-5]. For example, a

co-processed excipient containing microcrystalline cellulose (MCC; Avicel PH 102) and

mannitol was prepared by wet granulation with hydroxypropyl cellulose (HPC) using

high-shear mixing [3]. The prepared excipient exhibited the necessary characteristics of

pharmaceutical filler compared with co-processed lactose and calcium phosphate-

containing formulations. Both lactose and calcium phosphate can give rise to physical

and chemical problems (e.g. the Maillard reaction) [3]. A novel co-processed excipient

has been prepared by spray drying the aqueous slurry of MCC and mannitol to provide a

system with reduced lubricant sensitivity, higher compactibility and a lower tablet

ejection force profile, relative to its individual components or the physical mixture. The

prepared co-processed excipient exhibited reduced reactivity towards actives and is

CHAPTER FOUR


particularly useful as a binder for tablet formulations processed by direct compression

[4].

In order to overcome the problem of the loss in compressibility of MCC when used in

wet granulation formulations, silicon dioxide particles have been integrated with MCC

particles using a spray-drying process [5]. The co-processed excipient shows better

flowability, compressibility and disintegration properties compared to commercially

available MCC or a physical mixture of MCC and silicon dioxide, specifically in wet

granulation formulations. However, using the aforementioned co-processed excipients in

tablet formulations needs a disintegrant to enhance the disintegration and subsequent

release of the active pharmaceutical ingredients from the tablets [5].

There is increasing interest in exploring new commercial uses for chitin, a

polyglucosamine, which can exist in three polymorphic forms: α, β and γ; the most

abundant naturally occurring polymorph is α-chitin. Of the three polymorphic forms, α-

chitin has the highest compressibility [6]. Chitin is natural, non-toxic, non-allergenic,

anti-microbial, and biodegradable material and as such does not present any known health

risks [7, 8]. The compactibility values of α-chitin powder are very similar to those of

MCC and significantly higher when compared to dibasic calcium phosphate or

pregelatinized starch. This is because chitin is less plastic and more elastic than

microcrystalline cellulose, as well as being more plastic and elastic than dibasic calcium

phosphate [9].

Recently chitin has been used to prepare different co-processed excipients with a range of

metal silicates and silicon dioxide [10, 11]. The excipients obtained offer formulations

with the requisite physical properties (e.g. non-hygroscopic, highly compactable, and

highly disintegrable).

As a result of such modifications, tablet disintegration is

characterized by superiority in water uptake and penetration, with no gelling hindrance

effects [11]. Furthermore, chitin can be used at higher concentrations than commercially

available superdisintegrants without negatively affecting the disintegration properties

[10,11]. It is reported that commercially available superdisintgrants loose their function,

as disintegrants, when their concentration exceeds certain limits (3-15% w/w); thereby

excluding their use as fillers or binders in solid dosage formulations [12].

Mannitol is a naturally occurring sugar alcohol found in animals and plants; it is present

CHAPTER FOUR


in small quantities in almost all vegetables. An acceptable daily intake of mannitol has

not been specified by the World Health Organization (WHO) since the amount consumed

as a sweetening agent is not considered to represent a hazard to health. Mannitol is

widely used in pharmaceutical formulations and as such it is primarily used as a diluent

(10–90% w/w) in tablet formulations, where it is water soluble, non-hygroscopic and

produces a semi-sweet, smooth, and cool taste [13]. Because of its low hygroscopicity,

mannitol is potentially an excellent excipient since it is compatible with the majority of

active pharmaceutical ingredients. However, crystalline mannitol is excessively friable,

leading to the formation of fine particles that are particularly detrimental to its flow

properties. In addition, because of its compact crystal structure, mannitol obtained by

crystallization from water exhibits poor solubility. This slow dissolution rate is a major

disadvantage and thus restricts its use in pharmaceutical formulations [14]. Recently,

novel pharmaceutical formulations containing both α-chitin and crystalline mannitol have

been developed in order to eliminate such disadvantages [15]. It is expected that such

formulations will result in the co-processed excipient displaying no adverse effect on

human health, because the proposed novel co-processed excipient is produced in the

absence of any chemical reactions between the individual components [2]. As a result the

combination of chitin with mannitol (a non-hygroscopic inert material) may offer a

valuable and practical industrial choice as an excipient in terms of disintegration and

compaction properties [15].

The majority of commercially available co-processed excipients are produced by spray-

drying [16], which is a costly and complicated technique. In the present work, an easily

useable, dry or wet granulation procedure is expected to be advantageous for preparing a

co-processed excipient from crystalline mannitol and α-chitin that can be used as a multi-

purpose superdisintegrant, filler and binder in solid dosage formulations. From an

industrial perspective, the production of co-processed excipients using classical

techniques results in a less expensive method of manufacturing compared to spray drying.

Further, the machines used in such technique are practically available in almost every

industrial facility. Consequently, the use of such technique would not imply any further

costing to the manufacturer. The studies reported herein aim to test the foregoing

assumption and to characterize and optimize the composition and preparation procedure

CHAPTER FOUR


for mannitol/α-chitin mixtures. The overall properties, functionality and applications of

the co-processed mixture are also investigated.

4.2 Experimental

4.2.1. Materials

Commercial chitin, average molecular mass 1000 KD and degree of acetylation about

0.96, was obtained from Zhejiang Jiande Biochemical, (China). Crystalline grade

D-mannitol (Pearlitol), with a mean particle size of 160 m, was obtained from Roquette

(France). Purified water of British Pharmacopeia grade was obtained from the Jordanian

Pharmaceutical Manufacturing Co. (Jordan). Co-spray dried microcrystalline cellulose

with D-mannitol (Avicel® HFE 102) was obtained from FMC BioPolymer (Germany);

magnesium stearate from Mallinckrodt (USA) and Opadry OY-1350 film coat from

Colorcon (UK). All the active ingredients used were of pharmaceutical grade. These

included: amlodipine besylate (Matrix Lab., India), methyldopa (Xinshiji pharma, China)

and rosuvastatin calcium (Bicon, India). Aldomet

250 tablets (Merck & CO., Inc),

Norvasc

10 tablets (Pfizer Inc.) and Crestor

20 tablets (AstraZeneca UK Limited) were

obtained from a market in Jordan. All other reagents used were of analytical grade.

4.2.2. Methods

4.2.2.1. Preparation of Co-Processed Mannitol-Chitin

Three co-processed mixtures (each 1 kg) of mannitol and chitin of different ratios (1:9,

2:8, and 3:7, w/w) were prepared using different processing techniques i.e. direct mixing,

as well as spray, wet and dry granulation.

Direct mixing

The components of each mixture were individually passed through a 710 m mesh sieve

(Fritsch, Germany) and then mixed together for 5 min at 10 rpm using a 7.5 liter cubic

blender equipped with a motor drive machine (Erweka, Germany).

CHAPTER FOUR


Dry granulation

The three mixtures prepared by direct mixing were compacted using a roll compactor

equipped with DPS type rolls (TFC-labo, Vector Corporation, USA), set at about 5 MPa

roll pressure, 4 rounds/minutes roll speed and 20 rounds/minutes screw control speed.

The compacted powder was collected and sieved through a 710 m sieve using a milling

machine equipped with a motor drive machine. Finally the granules were mixed for 5 min

at 10 rpm using a 7.5 liter cubic blender equipped with a motor drive machine.

Spray granulation

A 20% (w/v) aqueous mannitol solution was prepared. Chitin was passed through a

710 m sieve and fluidized in a fluid bed granulator vessel (Strea 1, Niro Aeromatic,

Germany) using an air pressure and drying temperature of 1.5 bar and 60C, respectively.

The appropriate volumes of mannitol solution (0.5, 1, and 1.5 liter for 1:9, 2:8, and 3:7

(w/w) mannitol-chitin mixtures, respectively) were sprayed into the fluidized chitin at a

spray rate of 5 mL/min. The granules were then sieved and mixed using the same

parameters as for the dry granulation procedure.

Wet granulation

Different mannitol solutions (6, 12 and 16% w/v) were prepared by dissolving the

required quantity of mannitol to be used to prepare the mannitol-chitin mixtures (1:9, 2:8

and 3:7 w/w ratio, respectively) in sufficient amount of water to achieve a suitable

granulation end point. The sieved chitin was placed in granulation pan (Erweka,

Germany) and granulated with the mannitol solution using a mixing speed of 200 rpm.

The wet mass was passed through a 9.5 mm sieve. Granule drying was performed at 60C

using a drying oven (UT6200, Heraeous, Germany). The granules were sieved and mixed

using the same procedures as used for the dry granulation procedure.

CHAPTER FOUR


4.2.2.2 Characterization of Cop-MC

Fourier transform infrared spectroscopy (FT-IR)

FT-IR measurements were undertaken using an FT-IR instrument (Paragon 1000, Perkin

Elmer, UK) using thin pellets containing 1 mg of each sample dispersed in 100 mg of

KBr. The spectra were recorded at room temperature as an average of 30 scans, in the

400–4000 cm-1

range with a spectral resolution of 1 cm-1

. In order to minimize the effects

of traces of CO2 and water vapour from the atmosphere of the sample compartment, the

spectrometer was purged with N2.

X-ray powder diffractometry (XRPD)

The XRPD profiles were measured using an X-ray diffractometer (PW1729, Philips,

Holland). The radiation was generated using a CoK source and filtered through Ni

filters; a wavelength of 1.79025 Å at 40 mA and 35 kV was used. The instrument was

operated over the 2 range of 5-60o. The range and the chart speed were set at 2 × 10

3

cycles/sec and 10 mm/2θ, respectively.

Scanning-electron microscopy (SEM)

Sample morphology was determined using a scanning electron microscope (Quanta 200

3D, FEI, Eindhoven/Netherland) operated at an accelerating voltage of 1200 V. The

sample (0.5 mg) was mounted onto a 5×5 mm silicon wafer affixed via graphite tape to

an aluminum stub. The powder was then sputter-coated for 105 s at a beam current of

20 mA/dm3 with a 100 Å layer of gold/palladium alloy.

4.2.2.3 Testing of the Cop-MC Containing Tablets

The compressed tablets containing Cop-MC were tested for crushing strength (6D,

Schelenuiger tester, Germany), disintegration (2T31, Erweka tester, Germany) and

friability (Erweka tester, Germany) following the general tests in the British

Pharmacopeia [17].

CHAPTER FOUR


4.2.2.4 Physical and Chemical Properties of Cop-MC

Bulk density and particle size distribution

The bulk density and particle size distribution were measured using a powder volumeter

(SVM, Tapped volumeter, Erweka, Germany) and a powder particle size analyzer

(Vibratory sieve, shaker analysette 3PRO and 1000 to 63 m sieves, Fritsch, Germany),

respectively.

pH and water content measurements

The pH of a 5% (w/v) aqueous dispersion and powder water content were measured using

pH meter (Seven-multi pH-meter, Mettler, Switzerland) and titrator (DL38, Karl Fischer

Titrator, Mettler, Switzerland), respectively.

Hygroscopicity

Samples (each 2.5 g) were stored in desiccators containing water saturated salt solutions

at room temperature (20C) for 10 and 14 days. The media compositions were set

according to the Handbook of Chemistry and Physics [18] to obtain relative humidity’s

(RHs) of 52, 62, 75, 84 and 95% using Ca(NO3).4H2O, NH4NO3, NaCl, KCl and

Na2HPO4.12H2O, respectively. The samples were withdrawn after a fixed time period

and stored at 20C for 1 and 24 hr before weighing and calculating the percentage gain in

weight from the original weight under the different RH conditions.

4.2.2.5 Influence of Particle Size on Compression Characteristics

Samples of Cop-MC were passed through either 710 m or 853 m sieves and

individually dry-mixed with 0.5% w/w magnesium stearate for 3 minutes and then

compressed using a single punch tabletting machine (SFS, Chadmach machinery, India)

at different crushing strength values of: 30, 50, 70, 90, 110, 130 and 150 N, using a 9 mm

circular punch to produce tablets of 180 mg weight. The disintegration time and friability

were measured at each tablet crushing strength point. Avicel® HFE 102 NF was treated in

the same way and used as a reference.

CHAPTER FOUR


4.2.2.6 Effect of Lubricant Quantity on Tablet’s Physical Properties

Samples of Cop-MC were physically mixed for 3 minutes with different percentages of

magnesium stearate (0.25 - 5% (w/w)) in a 7.5 liter cubic blender equipped with a motor

drive machine. The powder was compressed at an adjusted upper punch scale of 25 KN,

in which a 8 mm circular punch was fitted and tablet weight was fixed at 180 mg. The

disintegration time and friability were measured.

4.2.2.7 Functionality

To study the functionality of the Cop-MC tablets of rosuvastatin calcium (RSC) were

prepared by different procedures including direct mixing as well as dry and wet

granulation. The tablets contained RSC (7.6% w/w), Cop-MC (91.7% w/w) and

magnesium stearate (0.7% w/w). For the direct mixing procedure (Formula 1), RSC and

Cop-MC were first mixed for 2 min and then magnesium stearate was added and further

mixed for another 3 minutes. For the dry granulation procedure (Formula 2), RSC (7.6%

w/w), Cop-MC (25% w/w, intra-granular) and magnesium stearate (0.2% w/w) were

compacted with a DP roll type using 10 MPa roll pressure, 3 rounds/minutes roll speed

and 43 rounds/minutes screw control speed, and then passed through a 710 m sieve. The

remaining amount of Cop-MC (66.7% w/w) was added and mixed for 2 minutes;

magnesium stearate (0.5% w/w) was added. The preparation was further mixed for 2

minutes. For the wet granulation procedure (Formula 3), RSC (7.6% w/w) and Cop-MC

(35% w/w, intra-granular) were granulated with 50% (w/v) ethanol solution, dried at

60oC, and then passed through 710 m. The remaining amount of Cop-MC (56.7%) was

added and mixed for 2 minutes; magnesium stearate (0.7%) was then added and the

preparation mixed for a further 2 minutes. The three formulations were compressed at

290 mg tablet weight, for which 10 mm shallow concave punches and dies were used.

Dissolution testing [19] (DT80; Erweka tester, Germany) was performed according to the

U.S. Food and Drug Administration published dissolution method [20] for rosuvastatin

calcium tablets. The percentage release of rosuvastatin calcium was determined

spectrophotometrically (Du-650i UV/Visible spectrophotometer, Beckman, USA) by

measuring the absorbance at a max of 240 nm.

CHAPTER FOUR


4.2.2.8 Compressibility of the Cop-MC (Kawakita Equation)

Cop-MC was compressed using a universal testing machine (RKM 50, PR-F system,

ABS Instruments, Germany) equipped with 12 mm round, flat face upper and lower

punches as well as dies. The punch speed was fixed at 10 mm/min. Different compression

forces from 80 to 390 MPa were applied. Three tablets were prepared to ensure

reproducibility. Compression was carried out at 400 mg tablet weight. The compression

behavior of the samples was evaluated using Kawakita analysis. The Kawakita equation

(Equation 1) is used to study powder compression using the degree of volume reduction,

C. The basis for the Kawakita equation for powder compression is that particles subjected

to a compressive load in a confined space are viewed as a system in equilibrium at all

stages of compression, so that the product of the pressure term and the volume term is a

constant [21]:

o

o

(V -V) abPC = =

V (1+bP) (1)

where Vo is the initial volume and V is the volume of powder column under an applied

pressure, P. The constants a and b represent the minimum porosity before compression

and plasticity of the material, respectively. The reciprocal of b defines the pressure

required to reduce the powder bed by 50% [22, 23]. Equation 1 can be re-arranged in

linear form as:

P P 1= +

C a ab (2)

The expression for particle rearrangement can be affected simultaneously by the two


product of the Kawakita parameters a and b, may hence be used as an indicator of particle

rearrangement during compression [24].

4.2.2.9 Compatibility Study of Cop-MC with Methyldopa

Differential scanning calorimetry (DSC 25, Mettler Instruments, Switzerland) can be

used for a wide range of pharmaceutical applications ranging from the characterization of

CHAPTER FOUR


materials to the evaluation of drug excipient interactions via the appearance, shift, or

disappearance of endothermic or exothermic peaks [25-27]. DSC was used to study the

compatibility of the methyldopa active pharmaceutical ingredient in a tabletted dosage

form with Cop-MC and magnesium stearate (Formula 4). The tablets were packed in

either open or closed glass containers and stored at 40C/75% RH for a 6 month period.

The reference formula was prepared without methyldopa according to Formula 4 using

the same composition ratio of excipients. All the samples were tested before and after

storage, under defined conditions. DSC samples were hermetically sealed in aluminum

pans and scanned over a range temperature of 0 to 300°C at a rate of 5°C/min. The

instrument was calibrated using indium and the calorimetric data was analyzed using

STAR software (version 9).

4.2.2.10 Applications

The Cop-MC was used to formulate methyldopa and amlodipine besylate active

ingredients into a tabletted dosage form; tablets were prepared using direct mixing. The

methyldopa formulation (Formula 4) comprised the active ingredient (63.3% in its

hydrated form), Cop-MC (32.8%), and magnesium stearate (0.6%). Tablets were film-

coated using Opadry OY-1350 (Colorcon-UK) coating material (3.3%) and sufficient

water as solvent. The amlodipine besylate formulation (Formula 5) comprised the active

ingredient (7.0% as besylate), Cop-MC (92.5%), and magnesium stearate (0.5%). 10 mm

shallow concave and 8 mm flat face beveled edge punches were used for tabletting the

methyldopa and amlodipine besylate containing formulations, respectively. Tablets of

Formulas 4 and 5 were tested for crushing strength, disintegration and dissolution.

Methyldopa tablets (250 mg) were further tested for their stability after being stored at

40oC/75% RH for 6 months using HPLC instrument equipped with a P1000 pump and a

UV1000 detector (TSP/USA). A stability indicating and validated HPLC method was

used to determine methyldopa, O-3-methylmethyldopa (synthetic impurity) and other

related compounds [28]. A mixture of 50% (v/v) aqueous methanol and 1% (v/v)

perchloric acid (350:650 v/v) was used as the mobile phase and an octyl silane column as

the stationary phase (Lichrosphere 100 RP-8, 250×4 mm, 10 m). UV detection at 230

CHAPTER FOUR


nm, a flow rate of 1 mL/min and a 20 L injection loop were used. The HPLC method

was initially tested for system suitability (i.e. peak symmetry, repeatability, and

resolution) and for validation parameters (i.e. specificity, recovery, stability in solution,

linearity and limit of quantitation (LOQ)) according to USP guidelines [29]. The stored

tablet samples in addition to methyldopa active ingredient (as a reference) were packed in

either open or close amber glass bottles. Aldomet

250 and Norvasc

10 tablets were

used as reference materials for comparison purposes. The U.S. FDA published

dissolution method [20] for amlodipine besylate tablets was adopted for the dissolution

analysis. The dissolution method states the use of USP apparatus II (Paddle), 75 rpm

speed, 500 mL of 0.01N hydrochloric acid as the dissolution medium and 10, 20, 30, 45

and 60 min sampling times. The dissolution testing of methyldopa tablets were

performed according to the United States Pharmacopeia (USP 32), following the

methyldopa tablet official monograph [30]. The dissolution system states the use of USP

apparatus II (Paddle), 50 rpm speed and 900 mL of 0.1N hydrochloric acid as the

dissolution medium. The percentage release of amlodipine besylate and methyldopa was

determined spectrophotometrically by measuring the absorbances at max of 250 (1st

derivative) and 280 nm, respectively.

CHAPTER FOUR



4.3.1 Co-Processed Mannitol-Chitin with Low Lubricant Sensitivity

Lubricant sensitivity is the ratio of the un-lubricated to the lubricated compactibility of

the tablet formulation. Addition of lubricant reduces the heat produced and tablet ejection

force during compression, which is related to the reduction in inter-particulate interaction

during compaction; as a result powder compactibility is decreased. Lubricant sensitivity

also refers to the reduction in interaction between the plastically deforming particles in

the powder, due to the addition of lubricant, which leads to a reduction in tablet crushing

strength [31].

Chitin powder exhibits poor flow and produces fragile tablets upon compression, while

pure crystalline mannitol displays undesirable compaction properties and results in tablet

capping. To obtain the optimal ratio of co-processed mannitol-chitin mixture, three

different ratios of mannitol: chitins were used: 10:90, 20:80 and 30:70 (w/w). These

mixtures were prepared by different processing techniques i.e. direct mixing, dry, spray

and wet granulation. The prepared granules were lubricated using different weight

fractions of magnesium stearate ranging from 0.25% to 5.0% (w/w). The mixtures were

compressed at 25 kN scale of the upper punch and the tablets obtained were tested for

crushing strength, friability and disintegration time. The results indicate that

improvements in the physical properties of mannitol and chitin mixtures follow the order:

wet and spray granulation > dry granulation > direct mixing. The mixtures prepared by

direct mixing have unacceptable physical properties (e.g. poor powder flow, powder non-

uniformity (segregation), friable and low crushing strength tablets). Additionally, the

results indicate that the properties of mannitol/chitin mixtures are improved by dry

granulation but they were still not optimal. Moreover it was noted that friability was

sensitive to the fraction of magnesium stearate added. As a result, excipients produced by

direct mixing and dry granulation methods were no longer used since the addition of

active ingredients having critical properties (e.g. poor flow, incompressible, fragile, etc)

could have a negative impact on compressed tablets.

The main objective thus became to find the most appropriate mixture that could be used

CHAPTER FOUR


to overcome the poor flow and weak compressibility of its components. The method of

integrating two components is an important factor in obtaining a suitable mixture that is

needed to act as a diluent for the active ingredient.

From the preliminary results physical mixing and direct compaction of the two

components proved unsatisfactory; consequently spray and wet granulation were used to

produce the new excipient, whereby the properties of the two components are able to

overcome poor flow and compression properties. In addition the compatibility of the

mixture towards lubrication sensitivity was tested.

In the case of spray and wet granulations, the physical properties were improved with

respect to the mannitol: chitin ratio used in the following order: 2:8 > 3:7 > 1:9 (w/w

mannitol/chitin). The mixtures prepared using ratios of 1:9 and 3:7 (w/w) showed

relatively high friability and sensitivity to the weight fraction of magnesium stearate

added as a lubricant. The optimal ratio with respect to physical properties improvement is

the 2:8 (w/w) ratio (mannitol: chitin). All the physical properties at this ratio prepared

using dry granulation as well as spray and wet granulation in comparison with

co-processed microcrystalline cellulose (Avicel HFE 102) as a reference are shown in

Figure 4.1.

CHAPTER FOUR


0

20

40

60

80

100

Cru

sh

ing

Fo

rce

(N

)

Spray granulation

Wet granulation

Dry granulation

Avicel HFE 102

a

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Dis

inte

gra

tio

n (

Se

co

nd

)

b

0.0

1.0

2.0

3.0

4.0

5.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0

Fri

ab

ilit

y (

%)

Amount of Magnesium Stearate (%w/w)

c

Figure 4.1 Plots of the physical properties (crushing strength, disintegration time and

friability) of the co-processed mannitol-chitin mixture prepared by different granulation

techniques versus the amount of magnesium stearate added.

It is clear from the data presented in Figure 4.1 that the physical properties of mixtures

prepared by spray and wet granulation are not very sensitive to the amount of magnesium

stearate added due to the presence of folding (e.g. high surface area) (Figure 4.2), while

those prepared by dry granulation and Avicel HFE 102 are relatively sensitive to the

lubricant content.

CHAPTER FOUR


A

b

C

d

Figure 4.2 SEM images of Cop-MC lubricated with (a) 0.5% and (b) 3.0% (w/w)

magnesium stearate; Avicel HFE 102 powder lubricated with (c) 0.5% and (d) 3.0%

(w/w) magnesium stearate.

For further investigation, the mixture prepared by wet granulation was used and the other

preparations were excluded because from a manufacturing process perspective, the

former is conventional and more practical compared with using spray granulation and/or

compaction.

4.3.2 Characterization of Cop-MC

4.3.2.1 Fourier Transform Infrared Spectroscopy (FT-IR)

The FT-IR spectra of mannitol, chitin, the corresponding 2:8 physical mixture and

Cop-MC are shown in Figures 4.3a, 4.3b, 4.3c and 4.3d, respectively. It is clear that the

FT-IR spectra of the physical mixture of mannitol and chitin (Figure 4.2c), is almost a

CHAPTER FOUR


superposition of the FT-IR profile contributed by mannitol and chitin. The dominance of

the principal bands of chitin in the physical mixture is a result of its high percentage in

the mixture (80%, w/w). The FT-IR spectra of Cop-MC (Figure 4.2d) showed almost the

same bands as the physical mixture, which suggests the absence of any detectable

chemical interaction and the formation of a new solid phase, as shown by scanning

electron microscopy.

Figure 4.3 FT-IR spectra of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-

chitin (2:8, w/w), and (d) Cop-MC.

4.3.2.2 X-Ray Powder Diffractometry (XRPD)

Figures 4.4a, 4.4b, 4.4c and 4.4d show the XRPD profiles of mannitol, chitin, the

corresponding 1:1 physical mixture and Cop-MC, respectively.

CHAPTER FOUR


0

10000

20000

30000

40000

5 15 25 35 45 55

Inte

ns

ity

(A

.U.)

2

a

b

c

d

Figure 4.4 XRPD profiles of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-

chitin (2:8, w/w), and (d) Cop-MC.

It is clear that the XRPD pattern of the physical mixture of mannitol and chitin is almost a

superposition of the patterns contributed by mannitol and chitin. In contrast, the

diffraction pattern of Cop-MC showed a reduction in the principal diffraction peaks

apparent in the XRPD patterns of the physical mixture, which suggests the formation of a

new solid phase.

4.3.2.3 Differential Scanning Calorimetry (DSC)

Figure 4.5 shows the thermal behavior of all samples investigated by DSC.

CHAPTER FOUR


a

e

d

c

f

b

mW50

°C40 60 80 100 120 140 160 180 200 220 240 260 280 300 320

exo

chitin vs ref.temp

24.12.2009 10:19:28

STARe SW 9.00

Lab: METTLER

Temperature (oC)

Ex

oth

erm

ic

Temperature (oC)

Hea

t fl

ow

(E

xo

therm

ic)


treated physical mixture of mannitol-chitin (2:8, w/w), (e) treated physical mixture of

mannitol-chitin (2:8, w/w) and (f) Cop-MC.

Mannitol exhibits an endothermic peak at about 167C (Figure 4.5a), which is retained

with high intensity in the physical mixture of mannitol and chitin (Figure 4.5c), but a

significant reduction in the intensity of the mannitol peak in the thermogram of the

Cop-MC occurs (Figure 4.5d) indicating that some of the mannitol is sequestered in the

chitin pores.

4.3.2.4 Scanning-Electron Microscopy (SEM)

SEM was used to investigate particle surface morphology (Figure 4.6). When comparing

the surface of chitin (Figure 4.6b) with the surface of the Cop-MC prepared using wet

granulation (Figure 4.6d), it is apparent that its native structure has changed from a

smooth, flat surface structure, with folded edges, to three-dimensional compacts for the

Cop-MC. This folding in the surface of the co-processed chitin creates a bigger surface

area which can accommodate a larger quantity of lubricant.

CHAPTER FOUR


a

b

c

d

e

Figure 4.6: SEM images of (a) mannitol, (b) chitin, (c) physical mixture of mannitol-

chitin (2:8, w/w), (d) Cop-MC and (e) Avicel HFE 102.

Figure 4.6e shows the surface of chitin-mannitol indicating the presence of inter-

particulate voids and channels. Figure 4.6c shows the surface of the AVICEL HFE 102,

which exhibits a smaller surface area due to the solid surface and the absence of folded

edges. This is the major reason underlying the clear increase in the disintegration time

and reduction in the crushing strength of the tablets containing AVICEL HFE 102, as a

result of increasing the quantity of magnesium stearate present. It is evident that the

Cop-MC excipient is not chemically altered; consequently it was used in further work.

CHAPTER FOUR


4.3.3 Physical Properties of Cop-MC

Some of the physical properties of the mixture prepared by wet granulation and sized

using two different sieves 710 m and 853 m (corresponding to mesh sizes of 22 and

18, respectively) were measured. These two sieves were selected in order to obtain

Cop-MC with particle size distributions capable of improving solid formulation

characteristics. Generally, in direct compression formulation, excipient flowability and

compaction performance are critical; therefore excipients used for such applications

should exhibit narrow particle size distributions with moderate-to-coarse particle size

(e.g. 100 to 200 µm) [32]. The granules obtained have a bulk density of 0.2-0.3 g/cm3

with particle size distributions of 20%, 45% and 30% in the range of < 180, 180 – 355,

> 355m, respectively.

36.7 %

0

3

6

9

12

15

45 55 65 75 85 95

% W

ate

r G

ain

ed

Relative Humidity (%)

Cop-MC/14 days

Cop-MC/14 days then 1 day at 20 C/45% RH

Avicel HFE 102/14 days

Avicel HFE 102/14 days then 1 day at 20 C/45% RH

Figure 4.7 The water gained by Cop-MC and Avicel HFE 102 kept in an open container

at different relative humidities and 20oC.

The pH of a 5% (w/v) aqueous dispersion is 7-8 and a water content of about 6% w/w.

Cop-MC was found to be slightly hygroscopic with a high moisture uptake capacity, but

only under extremely high humidity conditions (95% RH). This is expected and explains

the fast disintegration of the tablets in aqueous media. The data from the water gain vs.

relative humidity plots (Figure 4.7) clearly indicates that the Cop-MC absorbs a moisture

content that is up to 37% of its initial weight at 95% RH, but it loses most of this

moisture after equilibration at ambient conditions of 20oC and 45% RH for a day.

CHAPTER FOUR


4.3.4 Effect of Particle Size on Tablet Disintegration Time, Crushing Strength and

Friability

The disintegration time and friability versus the crushing strength for the tablets prepared

using Cop-MC powders passed through either 710 m or 853 m sieves are shown in

Figure 4.8. Generally, a reduction in particle size is associated with an increase in tablet

mechanical strength. The increase in mechanical strength of the tablets is attributed to an

increase in the surface area available for inter-particulate attraction, as the particles

become smaller [33]. However, when Cop-MC was used it was found that varying the

particle size had a minimal, or no, effect in increasing the mechanical strength of the

tablets produced. Generally, for materials with a tendency to fragment, the mechanical

strength of a tablet appears to be independent of particle size [34]. This is likely to be the

case for the Cop-MC particles which undergo fragmentation at an early stage of

compression; this normally results in a limited effect on tablet crushing strength when

varying the particle size. With respect to tablet disintegration, the Cop-MC, as evidenced

by the data in Figure 4.8, showed a unique and distinctive characteristic whereby

disintegration was independent of particle size and tablet crushing strength. Tablets,

produced from Cop-MC powders passed through either 710 m or 853 m sieves at an

upper bunch compression scale of 37-42 kN for each particle size, showed a superior

disintegration time, ranging from 5-145 seconds. This was achieved for tablet crushing

strength values ranging from 30-150 N, which suggests that capillary action is the

dominant mechanism for disintegration irrespective of the tablet crushing strength.

Therefore, the inter-particulate voids within the chitin particle structure in the Cop-MC,

as previously ascertained by scanning-electron microscopy, remain intact and unchanged

by varying the powder particle size and tablet crushing strength.

CHAPTER FOUR


0

30

60

90

120

150

180

210

240

-0.1

0.1

0.3

0.5

0.7

0.9

1.1

30 50 70 90 110 130 150

Dis

inte

gra

tio

n (

Se

co

nd

)

Fri

ab

ilit

y (

%)

Crushing Force (N)

Friability (853 mm)

Friability (710 mm)

Friability(Avicel HFE 102)

Disintegration Avicel HFE 102)

Disintegration (710 mm)

Disintegration (853 mm)

1800 sec

Figure 4.8 Effect of Cop-MC particle size on tablet crushing strength, disintegration time

and friability. The tablets were 9 mm in diameter and 180 mg in weight. All samples

were lubricated with 0.5% (w/w) magnesium stearate

Processing chitin with mannitol was found to cause alterations in chitin powder

compressibility and compactibility. Regarding powder compactibility, mannitol within

the Cop-MC mixture provides an effective means of obtaining hard tablets with low

friability while maintaining its super disintegration power, as deduced from the data in

Figure 4.8. While with the mannitolized microcrystalline cellulose (Avicel HFE 102), it

can be clearly observed that increasing the tablet crushing strength results in a significant

increase in disintegration time.

4.3.5 Kawakita Analysis (Compressibility)

Initial investigations of mannitol, chitin and Cop-MC using Heckel analysis indicated

non-log-linearity of compression data. Therefore, Heckel analysis was not adopted in this

work as it may result in misinterpretation of the estimated intercept and slope parameters

of the Heckel plots [10]. Therefore, in the present work, Kawakita analysis was adopted

to linearize the compression data. Figure 4.9 displays representative Kawakita plots for

mannitol, chitin and Cop-MC. The Kawakita constants a, b, ab and 1/b were calculated

from the intercept and slope of the plot (Table 4.1).

CHAPTER FOUR


y = 1.736x + 17.93R² = 1

y = 1.222x + 12.92R² = 1

y = 1.178x + 9.182R² = 1

0

100

200

300

400

500

600

700

800

50 100 150 200 250 300 350 400 450 500

P/C

Pressure (MPa)

Mannitol

Chitin

Cop-MC

Figure 4.9 Kawakita plot for mannitol:chitin (20:80) Prepared by a wet granulation

procedure. Tablets were 12 mm in diameter and 400 mg in weight.

Table 4.1 Kawakita Parameters.

Material Kawakita parameters

Slope Intercept a ab b 1/b

Mannitol 1.736 17.932 0.576 0.0558 0.0968 10.330

Chitin 1.223 12.927 0.818 0.0774 0.0946 10.570

*Cop-MC 1.178 9.182 0.849 0.1089 0.1283 07.795

*Co-processed mannitol-chitin (2:8 w/w) mixture

The constant (a), which represents the compressibility, is nearly the same for chitin and

the Cop-MC (a = 0.818 and 0.849, respectively) and is relatively low for mannitol (a =

0.576). Co-processing of chitin with mannitol has no significant increase in the

compressibility of chitin. This is because mannitol (20% of the Cop-MC content)

occupies only a limited area of the large surface pores of chitin. These pores are

responsible for the decrease in the volume of chitin powder upon compression [35]. The

value of the constant (1/b) for Cop-MC (7.795), which is an inverse measure of the

amount of plastic deformation occurring during the compression process [36], indicates

that the presence of mannitol increases the plastic deformation of chitin. The higher

degree of plastic deformation of Cop-MC during compression is most probably due to (a)

the formation of intermolecular hydrogen bonding between the plastically deformed

CHAPTER FOUR


adjacent particles within the chitin particles and (b) the presence of moisture within the

porous structure of chitin, which enforces the formation of hydrogen bonds and gives

Cop-MC high crushing strength values upon compaction and also acts as an internal

lubricant [37].

The relatively high value of ab for Cop-MC (0.1089), which is a measure of the extent of

particle rearrangement, indicates that, in the presence of mannitol, chitin exhibits a high

degree of packing during tablet compression. This implies that co-processing reduces the

surface micro-irregularities of chitin and facilitates particle re-arrangement during the

densification process of compaction. As a result, co-processing of chitin with mannitol

has positively improved the compression characteristics of chitin as shown by Kawakita

analysis.

4.3.6 Application


The functionality of Cop-MC was investigated by employing different processing

techniques (dry granulation, wet granulation and direct compression) for the preparation

of tablet dosage forms. Rosuvastatin calcium (RSC), a drug indicated for primary

hypercholesterolaemia, was selected as a model for this study. RSC is a hydrophobic

drug reported to be soluble and stable in the presence of the pH modifier tri-basic calcium

phosphate as one of the excipients used in the tablet matrix [38]. Crestor

20 tablet

commercial drug product was used as a reference. These tablets are composed of lactose

and microcrystalline cellulose as fillers, tri-basic calcium phosphate as alkalinizer and

stabilizer in addition to crospovidone as the disintegrant [38, 39]. Therefore, the use of

Cop-MC under neutral/alkaline conditions (pH of 7.0-8.0) is a suitable choice for RSC

tablet formulation [40-41]. The direct compression procedure for RSC with Cop-MC at a

dilution capacity of 7.6% (w/w) resulted in hard tablets with more than 90% drug release

within a 10 min time interval. The disintegration times for the RSC tablets prepared by

the three different procedures and Crestor

20 tablets were similar and lie in the 120-160

sec range. The uncoated tablets of RSC, obtained by using the three different methods of

preparation, have crushing strength values in the range of 90-120 N and friability values

CHAPTER FOUR


of 0.1-0.3%. The foregoing results indicate that the Cop-MC has an improved

compressibility, whether utilized in direct compression, dry granulation or wet

granulation formulations. Thus implying that Cop-MC can be used as a single excipient

acting as filler, binder and disintegrant in tablet formulations.

Some applications using Cop-MC as the only filler, binder and superdisintegrant were

also investigated. Two antihypertensive agents, amlodipine besylate (which is a

1,4-dihydropyridine calcium channel blocker) and methyldopa

(L-3-(3,4-dihydroxyphenyl)-2-methylalanine” an aromatic-amino acid decarboxylase

inhibitor), were selected as model drugs for this study as they have special requirements

in tablet formulation design. Due to the high strength and weak compactibility of

methyldopa powder, difficulties in the formulation of this active ingredient can occur e.g.

capping (i.e. “layering”) of the tablets during ejection in tabletting processing. In

addition, the particle size and shape of the active ingredient have a major impact on the

tablet compaction and binding properties during compression. Usually these unfavorable

characteristics mean that a granulation procedure has to be used for the preparation of the

tablets [42]. This is because direct compression procedures cannot overcome the

aforementioned characteristics by using sufficient quantities of suitable fillers, binder and

disintegrant while maintaining a low tablet weight. The 355 mg film coated Aldomet 250

tablets contain calcium disodium edetate, cellulose powder, anhydrous citric acid,

colloidal silicon dioxide, ethyl cellulose, guar gum and magnesium stearate in the tablet

core and D&C Yellow 10, hydroxypropyl methylcellulose, anhydrous citric acid, iron

oxide, propylene glycol, talc, and titanium dioxide for tablet coating [43]. On the other

hand, lactose is incompatible with amlodipine besylate (Maillard reaction) due to the

presence of a primary amine group in its chemical structure [44]. Therefore to achieve the

required binding, while maintaining other tablet physical properties, a multi-excipient

system is employed in the originator product “Norvasc® 10 tablets” using a high dilution

factor for the amlodipine besylate. The 400 mg tablets of Norvasc® 10 contain

microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch

glycollate and magnesium stearate [38]. The performance of Cop-MC in a direct

compression formulation containing a poorly compressible high strength drug, such as

methyldopa, and a low strength drug, such as amlodipine besylate, were investigated. The

http://www.rxlist.com/script/main/art.asp?articlekey=2575




CHAPTER FOUR


binding and super-disintegration properties, in addition to drug dissolution rate of the

tablets prepared, were examined and the results are summarized in Table 4.2. Direct

compression techniques were used to prepare the tablets in which Cop-MC was used as

the only binder, filler and disintegrant. Crushing strength values of the tablets obtained

from both formulations showed high internal binding and fast disintegration time. Full

drug release was obtained at 10 min dissolution time for both drugs. This indicates that

Cop-MC functions as a binding, disintegration and dissolution promoter. However, it is

worth mentioning that although methyldopa tablets showed super-disintegrating

characteristics this did not have an influence on their coating using an aqueous coating

system.

CHAPTER FOUR


Table 4.2 Physical properties of rosuvastatin 20 mg, methyldopa 250 mg and amlodipine 10 mg tablets.

Tested Parameter Rosuvastatin 20 tablets Methydopa 250 tablets Amlodipine 10 tablets

Formula 1 Formula 2 Formula 3 Crestor Formula 4 Aldomet Formula 5 Norvasc

Weight (mg) 290 315 450 355 200 400

Shape (mm) Round shallow biconvex of 9 mm diameter

Pink round

of 9 mm

diameter

Round

shallow

biconvex of 9

mm diameter

Round

shallow

biconvex of

9 mm

diameter

Round flat

faced beveled

edged of 8.mm

diameter

Elongated

octagon flat

faced beveled

edged

Crushing force (N) 119 120 120 * 140 * 110 112

Friability (%) 0.35 0.11 0.30 * 0.25 * 0.15 0.24

Disintegration time

(Seconds) 120 160 120 180 35 120 30 10

Dissolution

(%)

10 min

20 min

30 min

91

91

92

96

95

96

96

97

96

82

88

92

99

101

101

101

102

101

97

98

97

95

98

99

* Not performed as the tablets are film coated

CHAPTER FOUR


4.3.6.2 Stability of Active Ingredients in the Presence of Cop-MC

The DSC thermogram obtained for the initial analysis of pure methyldopa (Figure 4.10h)

shows an endothermic peak at about 124.5C which corresponds to the loss of water of

crystallization (sesqui-hydrate). The exothermic decomposition peak observed at about

300◦C is assigned to the melting of methyldopa. The DSC thermograms (Figsure 4.10f

and 4.10g) of a pure methyldopa sample stored for 6 months at 40◦C/75% RH, in open

and closed containers, showed an absence of secondary peaks corresponding to

impurities. The splitting obtained in the endothermic peak of the loss of the hydrate in the

120-130◦C temperature range is most likely to be due to different melting patterns of the

sesqui-hydrate in the methyldopa structure.

d

h

g

f

e

c

b

a

mW50

°C40 60 80 100 120 140 160 180 200 220 240 260 280

exo

DSC evaluation of dopanore 35

18.01.2010 15:27:10

STAR e SW 9.00

Lab: METTLER

Temperature (oC)

Exo

ther

mic

Figure 4.10 DSC scans of methyldopa 250 mg tablets (Formula 4) (a) after 6 months at

40oC/75% RH–close amber glass bottles, (b) after 6 months at 40

oC/75% RH–open

amber glass bottles, (c) initial analysis, (d) reference formula (without active ingredient)

at 40oC/75% RH–close amber glass bottles, (e) reference formula (without active

ingredient) at 40oC/75% RH–open glass amber bottles, (f) methyldopa at 40/75%

RH–close amber glass bottles, (g) methyldopa at 40oC/75% RH–open amber glass bottles

and (h) methyldopa initial analysis.

The DSC thermograms of Formula 4 (without active ingredient) samples (Figures 4.10d

and 4.10e) stored for 6 months at 40◦C/75% RH in open and closed containers showed

only one endothermic peak obtained at about 167◦C, which corresponds to mannitol. The

DSC scan of the samples of methyldopa 250 mg tablets (Formula 4) analyzed initially

(Figure 4.10c) and the samples stored at 40◦C/75% RH in closed (Figure 4.10a) and open

CHAPTER FOUR


amber glass bottles (Figure 4.10b) for 6 months, showed superimposition whereby no

secondary peaks were obtained upon storage under the accelerated conditions of

temperature and humidity (40◦C/75% RH).

Mixing methyldopa with Cop-MC lowers the decomposition peak temperature of

methyldopa from 300◦C to 270

◦C; this can be attributed to the interaction of two different

crystalline structures; such an interaction does not affect the stability of methyldopa as

indicated by the absence of new/additional DSC peaks (Figures 4.10-a, b and c) [45]. The

absence of new/additional peaks is an indication of the thermal stability and compatibility

of methyldopa in the tablet matrix containing Cop-MC.

The DSC study performed on methyldopa 250 mg tablets (Formula 4) was further

supported by a HPLC study.

Table 4.3 Stability data for α-methyldopa 250 mg film coated tablets at 40oC/75% RH.

Product Period

(months)

Assay

(%)

<5.0%+

from

initial

Impurities Profile (%) % Drug release

O-3 MD* ≤

1.0%

Total

(1.0%) 5 min.

10

min.

15

min

20

min

Methyldopa

Initial 99.6 0.01 0.19 -- -- -- --

6/close 102.2 0.01 0.22 -- -- -- --

6/open 99.6 0.01 0.21 -- -- -- --

Formula 4 Initial 99.4 0.01 0.18 95.6 99.5 100.5 100.8

1/close 97.7 0.01 0.20 92.2 98.5 101.5 102.1

1/open 98.1 0.02 0.16 75.4 92.6 96.1 98.0

2/close 97.4 0.01 0.17 92.9 97.6 100.0 100.2

2/open 99.9 0.02 0.16 75.8 97.8 100.5 101.1

3/close 98.4 0.01 0.22 92.0 98.9 99.8 102.4

3/open 98.6 0.01 0.17 79.2 96.8 99.5 100.0

6/close 99.2 0.01 0.16 89.3 96.4 98.4 99.8

6/open 98.2 0.01 0.31 88.2 95.5 98.3 99.4

Aldomet 250

Initial 100.9 0.01 0.14 91.6 101.2 102.1 101.9

6/close 97.8 0.01 0.29 83.4 94.7 99.1 100

6/open 98.0 0.01 0.27 57.1 77.5 90.0 95.3

*O-3 MD represents O-3-methylmethyldopa impurity. + According to ICH guideline for stability testing of new drug substances and products [39].

HPLC was used to investigate the chemical stability and compatibility of the tablets

containing methyldopa and Cop-MC, according to Formula 4. The HPLC method was

initially validated before use and the results showed a good separation between

methyldopa and O-3-methylmethyldopa related compound (the resolution R1 is more than

3) and the relative standard deviation of replicate injections is less than 2%. In addition,

CHAPTER FOUR


analyses of samples obtained from a stress-testing study (0.1N NaOH, 0.1N HCl, and

0.3% H2O2 at 25oC for 10 days) in solution indicated that the HPLC method is stability

indicating by a significant decrease in percentage assay of methyldopa in the basic media

and in the presence of hydrogen peroxide as oxidizing agent (35% and 89% w/w,

respectively). The accuracy of the method was investigated by testing 6 different sample

preparations containing methyldopa at two different concentrations (5 and 25 mg/100

mL) for measuring the percentage impurities and percentage assay, respectively. The

percentage recovery and RSD for 6 replicates are within the range of 98.1 to 102.9% and

0.3 to 1.4%, respectively. The method is linear over a concentration range of 1.3–50.0

mg/100 mL with an r2 value of > 0.999. The LOQ value is 0.7 mg/100 mL. Table 4.3

shows the analytical data obtained for methyldopa 250 mg tablet (Formula 4) samples

stored in open and close amber glass bottles at 40C/75% RH for 6 months. Pure

methyldopa and Aldomet® 250 tablets were treated in the same manner and analyzed as a

reference for this study. No significant decrease in the assay of methyldopa 250 tablets

according to Formula 4 was observed upon storage under the accelerated condition of

temperature and humidity (40C/75% RH).

Co-processing of α-chitin with crystalline mannitol significantly improves the

performance and functionality of both components. This offers a potential use of this co-

processed additive as a single tablet excipient displaying super-disintegrating properties.

The mechanical strength of the tablets and lubricant sensitivity were found to be

dependent upon the mannitol content and the processing technique used in the

preparation of the co-processed excipient.

CHAPTER FOUR


A

B

C

mA

U

a

b

c m

AU

a

b

c

Time (Minute)

mA

U

a

b

c

Figure 4.11 HPLC chromatograms of (A) methyldopa, (B) methyldopa 250 mg tablets

(Formula 4) and (C) Aldomet 250 mg tablets. Where (a) is the initial chromatogram (no

incubation), and (b)/(c) after 3 and 6 months incubation at 40oC/75% RH, respectively in

closed containers.

A small increase in the total impurities for samples of Formula 4, stored in open amber

glass bottles at 40C/75% RH for 6 months, was observed when compared to the samples

stored in closed amber glass bottles and Aldomet®

250 tablets (Table 4.3, Figure 4.11).

CHAPTER FOUR


4.4 Conclusions

The functionality of the Cop-MC is not affected by the tablet preparation procedure

whether it is direct mixing or dry/wet granulation. Utilization of Cop-MC, as an

excipient, in tablet formulations containing active pharmaceutical ingredients, offers

excellent chemical stability, binding and disintegration properties.

CHAPTER FOUR


4.5 References

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Lieberman HA, Lachman L, Schwartz JB, editors. Pharmaceutical dosage forms: Tablets,

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[2] Block LH, Moreton RC, Apte SP, Wendt RH, Munson EJ, Creekmore JR, Persaud IV,

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Maryland, USA: United States Pharmacopeia Convention Inc; 2009. p. 1026-1028.

[3] Westerhuis JA, de Haan P, Zwinkels J, Jansen WT, Coenegracht PJM, Lerk CF.

Optimisation of the composition and production of mannitol/microcrystalline cellulose

tablets. Int J Pharm. 1996; 143:151-162.

[4] Jian-Xin LI, Brian C, Thomas R. Co-processed microcrystalline cellulose and sugar

alcohol as an excipient for tablet formulations, Applicant: FMC Corp. (US), European

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[5] Sherwood BE, Hunter EA, Staniforth JH. Pharmaceutical excipient having improved

compressibility, Applicant: Edward H Mendell Co. Inc. (US), United States Patent

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[6] Muzzarelli RAA. Chitin. Pergamon Press. Oxford; 1977.

[7] Safety data for chitin, http://msds.chem.ox.ac.uk/CH/chitin.html, access date:

1/7/2010.

[8] Uragami T, Tokura S. Material science of chitin and chitosan. New York: Springer

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[9] Mir VG, Heinämäki J, Antikainen O, Revoredo OB, Colarte AI, Nieto OM, Yliruusi J.

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[10] Rashid I, Daraghmeh N, AL Remawai M, Leharne SA, Chowdhry BZ, Badwan A.

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[11] Rashid I, Al-Remawi M, Eftaiha A, Badwan A. Chitin-silicon dioxide coprecipitate

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superdisintegrating agent made from physically modified chitosan with silicon dioxide.

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[13] Armstrong NA. Mannitol. In: Rowe RC, Sheskey PJ, Owen SC, editors.

Pharmaceutical Excipients. USA: Pharmaceutical Press and American Pharmacists

Association; 2006. p. 439-453.

[14] Erik L, Philippe L, Jose L. Pulverulent mannitol and process for preparing it,

Applicant: Roquette Freres, Erik L, Philippe L, Jose L, United States Patent Office,

Patent No.: 6,743,447.

[15] Daraghmeh NH, Al Omari MM, Badwan AA. Pharmaceutical excipient, method for

its preparation and use thereof. European Patent Office (EPO). Patent Filed.

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coprocessinf. In: Katdsre A, Chaubal MV, editors. Excipient development for

pharmaceutical, biotechnology, and drug delivery systems. New York, London: Informa

healthcare; 2006. p. 123.

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British pharmacopeia. London: The Stationary Office. Volume IV, Appendixes XIIA,

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[18] Weast RC, Handbook of Chemistry and Physics. 55th edition, CRC Press; 1974–

1975.

[19] Dissolution <711>. United States Pharmacopeia and National Formulary (USP32-

NF27). Rockville, MD: US Pharmacopoeia Convention. Volume 1; 2009. p. 263-271.

[20] Dissolution method. U.S. FDA, Rockville. 2010. http://www. access data.

fda.gov/scripts/cder/dissolution/index.cfm. Accessed 4-Feb-2010.

[21] Kawakita K, Ludde KH. Some considerations on powder compression equations.

Powder Technol. 1971; 4:61–68

[22] Shivanand P, Sprockel OL. Compaction behaviour of cellulose polymers. Powder

Technol. 1992; 69: 177–184.

[23] Lin C, Cham T. Compression behaviour and tensile strength of heat-treated

polyethylene glycols. Int J Pharm. 1995; 118:169–179.

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[24] Nordström J, Klevan I, Alderborn G. A particle rearrangement index based on the

Kawakita powder compression equation. J Pharm Sci. 2008; 98:1053-1063.

[25] Giron D. Applications of thermal analysis in the pharmaceutical industry. J Pharm

Biomed Anal 1986; 4:755-770.

[26] Botha SA, Lotter AP. Compatibility study between naproxen and tablet excipients

using differential scanning calorimetry. Drug Dev Ind pharm. 1990; 16:673–683.

[27] Lin SY, Han RY. Differential scanning calorimetry as a screening technique to

determine the compatibility of salbutamol sulfate with excipients. Pharmazie. 1992;

47:266–268.

[28] Badwan AA. The Jordanian Pharmaceutical Manufacturing Co., Unpublished data.

[29] Validation of compendia procedures <1225>. In: United States Pharmacopeia and

National Formulary (USP32-NF27). Rockville, MD: US Pharmacopoeia Convention.

Volume I; 2009. p: 733-736.

[30] Methyldopa tablets. In: United States Pharmacopeia and National Formulary

(USP32-NF27). 2009. Rockville, MD: US Pharmacopoeia Convention. Volume 3; 2009.

p. 2942.

[31] Qiang D, Gunn J, Zong Z, Buckner I. Evaluating the effect of lubrication on powder

compaction with the compression calorimeter. AAPS Journal. 2009; 11(S2).

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2010.

[32] Carlson GT, Hancock BC. A comparison of physical and chemical properties of

common tableting diluents. In: Katdsre A, Chaubal MV, editors. Excipient development

for pharmaceutical, biotechnology, and drug delivery systems. New York, London:

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[33] Nyström C, Alderborn G, Duberg M, Karehill P-G. Bonding surface area and

bonding mechanism-two important factors for the understanding of powder

compactibility. Drug Dev Ind Pharm. 1993; 19:2143-2196.

[34] Alderborn G, Börjesson E, Glazer M, Nyström C. Studies on direct compression of

tablets. XIX. The effect of particle size and shape on the mechanical strength of sodium

bicarbonate tablets. Acta Pharm Suec. 1988; 25:31-40.

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[35] Paronen P, Iilla J. Porosity-pressure functions. In: Alderborn G, Nyström C, eds,

Pharmaceutical Powder Compaction Technology. New York, NY: Marcel Dekker Inc;

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[36] Adetunji OA, Odeniyi MA, Itiola OA. Compression, Mechanical and Release

Properties of Chloroquine Phosphate Tablets containing corn and Trifoliate Yam Starches

as Binders. Trop J Pharm Res. 2006; 5: 589-596

[37] Zhang Y, Law Y, Chakrabarti S. Physical properties and compact analysis of

commonly used direct compression binders. AAPS Pharm Sci Tech 2005; 4, Issue 4,

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[38] Summary of product characteristics (SPC) for Crestor® 20 and Istin

® 10 tablets. In:

Electronic Medicines Compendium. 2009 edition, Datapharm Communications Ltd,

Leatherhead, United Kingdom. http://emc.medicines.org.uk/default.aspx. Accessed 2

March 2010.

[39] Richard CJ, Alfred WN. Pharmaceutical composition comprising A HMG COA

reductase inhibitor, Applicant: Astrazeneca AB (SE), European Patent Office. Patent No.:

EP1223918.

[40] Fritz B, Adriaan DSP, Martin S. Crystalline forms of rosuvastatin calcium salt,

Applicants: Ciba SC Holding AG, Fritz B, Adriaan DSP, Martin S, European Patent

Office, Patent No.: WO2006079611.

[41] Shlomit W, Valerie N-H, Shalom S. Crystalline rosuvastatin calcium, Applicant:

Teva Pharma, Shlomit W, Valerie N-H, Shalom S, European Patent Office, Patent No.:

WO2008036286.

[42] KOICHI W, HIKARU F. Tablet Formulation, Applicant: NOVO NORDISK AS.

(DK), European Patent Office, Patent No.: US2009252790

[43] The Internet Drug Index (RxList). 2010. http://www.rxlist.com/aldomet-drug.htm .

Accessed 4-Feb-2010.

[44] Abdoh A, Al-Omari MM, Badwan AA, Jaber AMY. Amlodipine besylate-excipients

interaction in solid dosage form. Pharm Dev Tech. 2004; 9:15-24.

[45] Agatonovic-Kustrin S, Markovic N, Ginic-Markovic M, Mangan M, Glass BD.

Compatibility studies between mannitol and omeprazole sodium isomers. J Pharm

Biomed Anal. 2008; 48: 356–360.

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[46] ICH Topic Q1 A (R2) Stability Testing of New Drug Substances and Products.

European Medicine Agency (EMEA). 2003.

http://www.ema.europa.eu/pdfs/human/ich/273699en.pdf . Accessed 4-Feb-2010.

CHAPTER FIVE


5. A NOVEL ORO-DISPERSIBLE TABLET BASE:

CHARACTERIZATION AND PERFORMANCE

5.1 Introduction

Tablets are widely used in medication due to their convenience with respect to self-

administration and ease in manufacturing [1]. To improve the performance, functionality

and quality of pharmaceutical tablets, various excipients are used in their preparation [2].

However, pediatric, geriatric and mentally ill patients experience difficulties in

swallowing conventional tablets, which leads to poor patient compliance. To overcome

this deficiency, oro-dispersible tablet (ODT) formulations have been developed [3, 4]. In

the European Pharmacopoeia, an ODT is defined as a tablet to be placed in the mouth

where it disperses rapidly before being swallowed in less than 3 minutes [5], while the

FDA consider it as a solid oral preparation that disintegrates rapidly in the oral cavity

with an in vivo disintegration time of approximately 30 seconds or less [4]. ODTs are

advantageous due to their administration without water, rapid onset of action and

improved bioavailability [6, 7]. Various ODT technologies including Orasolv/DuraSolv

(by direct compression (DC)), Zydis (by freeze drying), FlashTab (Eudragit-

microencapsulation and effervescent couple), FlashDose (cotton candy process) and

WowTab (compression moulding process) have been patented [8, 9]. ODTs are highly

friable, due to their compaction at lower crushing force compared to conventional tablets,

resulting in rapid disintegration; therefore they are commonly packed in special

packaging materials [10]. A high level of super-disintegrant (up to 20% w/w) is usually

used in ODT preparations to enhance their disintegration properties. Additional

excipients including a suitable filler, binder, lubricant, sweetener and color may be added

to improve product properties [6, 11].

Mannitol, in crystalline, granulated, or spray dried form, is commonly used in ODT tablet

formulations due to its sweet cool taste, compatability with a range of active

pharmaceutical ingredients (APIs), non-hygroscopicity, and the fact that its metabolism

does not increase blood sugar levels [12-14]. Unlike crystalline mannitol, spray dried

mannitol is highly compactible, non-friable, and quick dissolving, which facilitates it use

in DC formulation which facilitate its use in ODTs. Furthermore, crystalline mannitol is

CHAPTER FIVE


widely used in wet granulation (WG) processes due to its low cost and availability [15-

17]. -Chitin plays several important roles in tablet formulations because it is non-toxic,

non-allergenic, anti-microbial, non-reactive and biodegradable. Its disintegration power is

mainly dependent upon a high water uptake rate. Therefore, chitin can be used over a

higher concentration range than many commercially available disintegrants without

negatively affecting other tablet properties. However, chitin powder shows poor

compactibility. -Chitin is the most abundant form among the three identified

polymorphs of chitin (-, - and -). It is the second most abundant polysaccharide on

earth after cellulose [18, 19].

Co-processing of pharmaceutical excipients is performed using specialized

manufacturing processes such as spray drying or melt extrusion in order to produce a

single excipient with multiple functionalities. In addition co-processing can be utilized

for improving the undesirable physico-mechanical properties of excipients and their

performance and is generally undertaken by using a combination of plastic and brittle

excipients [20]. For example, chitin, a plastic material, has been successfully used to

prepare different excipients via co-processing with diverse brittle materials including

mannitol, metal silicates and silicon dioxide [21-23]. In all cases co-processing was

achieved by incorporating the brittle material (≤ 30% w/w) inside the pores of chitin (≥

70% w/w) using an aqueous vehicle. The result of the foregoing studies showed that the

extremely large surface pores of chitin were not fully accommodated by the guest

materials and thus chitin preserved its functionality as a disintegrant. Moreover, the

co-processed excipients obtained displayed enhanced physical properties, functionality

and performance (e.g. no-hygroscopicity and highly compactable/disintegrable) [21-23].

Recently, a European patent (EP2384742) describing a novel co-processed single

excipient comprising different ratios of chitin and mannitol has been published [24]. This

novel co-processed excipient offers a valuable and practical industrial choice in terms of

super-disintegration and compaction properties of tablet dosage forms. Furthermore, an

article describing the characterization and application of such a novel co-processed

excipient in immediate release tablet formulations has been reported in the literature [23].

In the aforementioned study, the tablets prepared by using the co-processed excipient

chitin-mannitol (80:20 w/w) and different APIs displayed excellent chemical stability,

CHAPTER FIVE


binding, and disintegration properties.

The advantage of using chitin and mannitol in conventional tablets [23] proofs the use of

such combination in ODT formulation. Due to the ease of manufacturing, ability to

produce fast disintegration / dissolving properties and the ability of producing hard

tablets makes this a target to test the suitability to offer an excipient base for ODTs. Roll

compaction (RC) or WG may then be used to prepare the excipient using mannitol and

chitin. The studies reported herein aim to test the foregoing hypothesis and to

characterize the excipient obtained by using a higher ratio of mannitol to chitin than used

in the previous work [23] by applying RC and WG techniques. The functionality, loading

capacity, compatibility and applications of the obtained excipient with different APIs are

also reported.

5.2 Experimental

5.2.1 Materials

α-Chitin of average molecular weight 1000 KD, degree of acetylation of about 0.96 and a

mean particle size of 90 m (Zhejiang Jiande Biochemical, China) and D-mannitol

(Pearlitol), crystalline grade, with a mean particle size of 160 µm (Roquette, France) were

used Purified water of British pharmacopeia grade, Mannogem EZ and Pharmaburst C1

(SPI, France), Isomalt galenIQTM 721 (BENEO-Palatinit GmbH (Germany), PanExcea

MHC200G (Avantor Performance Materials, Inc./USA), sodium stearyl fumarate (JRS,

USA) and Crospovidone (Polyplasdone XL) with an average particle size of 110 – 140

(ISP, USA) were also used. All active pharmaceutical ingredients employed i.e.,

montelukast sodium (Matrix Lab., India), domperidone (Xinshiji pharma, China) and

metronidazole (Hubei Max Pharma, China) were of pharmaceutical grade. All other

excipients and reagents used were of pharmaceutical or analytical grades, respectively.

5.2.2 Methods

5.2.2.1 Preparation of Co-Processed Mannitol-Chitin Excipient

Three co-processed mixtures (each 1 kg) of chitin and mannitol of different ratios (1:9,

2:8 and 3:7 w/w) were prepared using different processing techniques i.e., direct mixing,

CHAPTER FIVE


RC and WG.

Direct mixing

The three mixtures were separately passed through a 1000 m mesh sieve (Fritsch,

Germany) and then mixed for 5 min at 10 rpm using a 1 liter cubic blender equipped with

a motor drive machine (Erweka, Germany).

Roll compaction

The three mixtures prepared by direct mixing were compacted using a roll compactor

equipped with DPS type rolls (TFC-labo, Vector Corporation, USA), set at about 5 MPa

roll pressure, 4 rounds/minutes roll speed and 20 rounds/minutes screw control speed.

The compacted powders were collected and passed through either the 710 m or

1000 m sieves using a milling machine equipped with a motor drive machine. Finally

the granules were mixed for 5 min at 10 rpm using a 1 liter cubic blender equipped with a

motor drive machine.

Wet granulation

350, 450 and 550 ml of 14.5% (w/v) of aqueous mannitol solutions were used as

granulating agents to prepare the chitin-mannitol mixtures (1:9, 2:8 and 3:7 w/w ratio,

respectively). The sieved chitin and the remaining quantity of mannitol were placed in

granulation pans (Erweka, Germany) and granulated with the mannitol solution using a

mixing speed of 150 rpm. The wet masses were passed through a 9.5 mm sieve. Drying

was performed at 60C using a drying oven (UT6200, Heraeous, Germany). The granules

were passed through the 1000 m sieve and mixed using the same procedures as used for

the RC preparation.

5.2.2.2 Characterization of co-processed chitin-mannitol (Cop-CM)

Fourie-transform infrared spectroscopy (FT-IR)

FT-IR measurements were undertaken using an FT-IR instrument (Paragon 1000, Perkin

CHAPTER FIVE


Elmer, UK) by means of thin pellets containing 1 mg of each sample dispersed in 100 mg

of KBr. The spectra were recorded at room temperature as an average of 30 scans, in the

400–4000 cm-1

range with a spectral resolution of 1 cm-1

. In order to minimize the effects

of traces of CO2 and water vapour from the atmosphere of the sample compartment, the

spectrometer was purged with nitrogen.

X-ray powder diffractometry (XRPD)

The XRPD profiles were measured using an X-ray diffractometer (PW1729, Philips,

Holland). The radiation was generated using a CoK source and filtered through Ni

filters; a wavelength of 1.79025 Å at 40 mA and 35 kV was used. The instrument was

operated over the 2θ range of 5-60o. The range and the chart speed were set at 2 × 103

cycles/sec and 10 mm/2θ, respectively.

Differential scanning calorimetry (DSC)

Samples ( 5mg) were hermetically sealed in aluminum pans and scanned over a range

temperature of 0–300°C at a rate of 5°C/min (DSC 25, Mettler Instruments). The

instrument was calibrated using indium and the calorimetric data were analyzed using

STAR software (version 9)

Scanning-electron microscopy (SEM)

The morphology of the samples were determined using a scanning electron microscope

(Quanta 200 3D, FEI, Eindhoven/Netherland) operated at an accelerating voltage of 1200

V. The sample (0.5 mg) was mounted onto a 5×5 mm silicon wafer affixed via graphite

tape to an aluminum stub. The powder was then sputter-coated for 105 s at a beam

current of 20 mA/dm3 with a 100 Å layer of gold/palladium alloy.

Angle of repose

Angle of repose (q) was determined using the funnel method [25]. The sample blends

were poured through a funnel that could be raised vertically until a maximum cone height

(h) was obtained. Radius of the heap (r) was measured and then q was calculated using

CHAPTER FIVE


the formula:

q = tan−1

h/r (1)

Particle size

The particle size distributions for all samples were measured by using a Malvern

Mastersizer 2000 instrument (Malvern Instruments Ltd, Worcestershire, UK).

Approximately 5 mL of powder was used for each measurement. The air pressure was set

at 2.0 bar, and the feed rate was set at 50%. The particle size distributions D10, D50 and

D90 were recorded. Each sample was measured 3 times.

Bulk density (BD) and tapped density (TD) [25]

Approximately 100 mL of powder was gently poured into a tarred graduated cylinder and

the initial volume and weight of the material recorded. The graduated cylinder is placed

on a tap density tester and the final volume is recorded after 200 taps. BD and TD are

calculated by dividing the initial and final volume of powder by the weight of powder,

respectively.

Water content

The water content of the powders was measured using a DL38, Karl Fischer Titrator

(Mettler Toledo-Switzerland).

Hygroscopicity

Samples (2.5 g) were stored in desiccators containing water saturated salt solutions at

room temperature (20C) for 10 and 14 days. The media compositions were set according

to the Handbook of Chemistry and Physics [26] to obtain relative humidity’s (RHs) of 52,

62, 75, 84 and 95% using Ca(NO3).4H2O, NH4NO3, NaCl, KCl and Na2HPO4.12H2O,

respectively. The samples were withdrawn after a fixed time period and kept at 20C for

1 and 24 hr before weighing and calculating the fractional gain in mass compared to the

original mass under the different RH conditions.

CHAPTER FIVE


2.2.3 Physical and chemical properties of tablets prepared from Cop-CM

Crushing force, disintegration and friability

The crushing force (6D, Schelenuiger tester, Germany), disintegration (2T31, Erweka

tester, Germany) and friability (Erweka tester, Germany) were performed following the

general tests in the British Pharmacopeia [27].

Influence of particle size on tablet properties

Samples of Cop-CM powders were passed using either 710 m or 1000 m sieves and

individually mixed with 1.0% (w/w) of sodium stearyl fumarate as a lubricant and then

compressed using a single punch tabletting machine (SF3, Chadmach Machinery, India)

at different crushing force values of 30, 50, 70, 90, 110, 130 and 150 N, using a 10 mm

circular punch to produce tablets of 250 mg weight. The disintegration time and friability

were measured at each tablet crushing force point. Some of the commercially available

ODT bases (Pharmaburst C1, Isomalt galenIQTM

721, Mannogem EZ and PanExcea

MHC 200G) in addition to Mannogem EZ and 3% crospovidone, Isomalt galenIQTM

721

and 3% crospovidone powders were lubricated using 1% w/w sodium stearyl fumarate

and used as reference materials.

Moisture uptake studies

Moisture uptake studies were conducted in order to assess the physical stability of the

ODTs composed of Cop-CM base. Twenty tablets were kept in a desiccator over calcium

chloride at 37C for 24 hours. The tablets were then weighed and exposed to 75% relative

humidity, at room temperature for 14 days. The required humidity was achieved by the

use of saturated sodium chloride solution at the bottom of the desiccators for 72 hours.

Tablets were weighed and the fractional increase in mass was recorded [26].

Wetting time

A piece of tissue paper (8 cm in diameter), folded twice was placed in a Petri dish (8.5

cm in diameter) containing 6 ml of water. One tablet was carefully placed on the surface

CHAPTER FIVE


of the tissue paper and allowed to wet completely [26]. The time required for the water to

reach the upper surface of the tablet was recorded as the wetting time.

Loading capacity

A study was undertaken to measure the impact of the API load on the performance of the

Cop-CM as tablet excipient. Tablets were prepared by DC using a SF3 single punch

tablet press machine equipped with D-type tooling. The seven experiments were

performed using Cop-CM and metronidazole, containing, 0%, 10%, 30%, 50%, 70, 90

and 100% (for comparison) of metronidazole lubricated with 0.3% sodium stearyl

fumarate. The prepared tablets were circular in shape with a diameter of 12 mm and a

mass of 500 mg. Tablets from each experiment were evaluated for crushing force and

disintegration time.

Functionality

To investigate the functionality of the Cop-CM, two API model as small strength tablets

were studied including montelukast sodium (Monte) and domperidone (Domp). The

tablets for the two APIs were prepared by DC, RC as well as WG methods. The Monte

and Domo tablets contained 1.77% and 3.4% of API and 94.7% and 93.1% of Cop-CM,

respectively. In addition, both APIs formulations contained strawberry powder (2.0%),

aspartame (0.5%) and sodium stearyl fumarate (1.0%). For the DC experiments, Monte

and all excipients, except sodium stearyl fumarate, were first mixed for 2 min and then

sodium stearyl fumarate was added and further mixed for another 2 min.

For the RC procedure, Monte (1.77% w/w), Cop-CM (25% w/w, intra-granular) and

sodium stearyl fumarate (0.6% w/w) were compacted by employing a DP roll type

compaction using 10 MPa roll pressure, 3 rounds/minutes roll speed and 43

rounds/minutes screw control speed and then passed through a 1000 m sieve. The

remaining amount of Cop-CM was added and mixed for 2 min followed by the addition

of sodium stearyl fumarate (0.4% w/w). The powder was then further mixed for 2 min.

For the WG procedure, Monte (1.77% w/w) and Cop-CM (35% w/w, intra-granular) were

granulated with 50% (w/v) ethanol in water, dried at 60oC, and then sieved using the

CHAPTER FIVE


1000 m sieve. The remaining amount of Cop-CM was added and mixed for 2 min;

sodium stearyl fumarate (1%) was then added and mixed for a further 2 min. The same

procedures were repeated for Domp. The prepared mixtures for each API were

compressed at 300 mg tablet weight, for which 10 mm shallow concave punches and dies

were used. Dissolution tests (DT-80; Erweka tester, Germany) for Monte and Domp were

performed according to the U.S. Food and Drug Administration [28, 29] and British

Pharmacopeia [30] published dissolution methods. The released fraction of Monte and

Domp were determined spectrophotometrically (Du-650i UV/Visible spectrophotometer,

Beckman, USA) by measuring the first derivative absorbance modes at 290 nm for Monte

and absorbance mode at 280 nm for Domp.

Compressibility

Mannitol, chitin and Cop-CM powder samples were compressed using a universal testing

machine (RKM 50, PR-F system, ABS Instruments, Germany) equipped with 12 mm

round, flat face upper and lower punches as well as dies; punch speed was fixed at 10

mm/min. Different compression forces from 80 to 390 MPa were applied. Three tablets

were prepared to ensure reproducibility. Compression was carried out at 400 mg tablet

weight. The compression behavior of the samples was evaluated using Kawakita analysis.

[31-34].

Stability studies

Monte and Domp tablets prepared by DC were packed in aluminum/aluminum strips and

stored at 25oC/60% RH and 40°C/75% RH for 24 and 6 months, respectively. At different

interval times, tablets were withdrawn and tested for dissolution and content of API and

its related substances by stability-indicating and validated HPLC methods [35-37]. The

HPLC instrument was equipped with a P1000 pump and a UV1000 detector (TSP/USA).

For Monte tablets, a mixture of acetate buffer (0.385% ammonium acetate in water

adjusted with acetic acid to pH 3.5) and methanol (15:85, v/v) was used as the mobile

phase and an octadecylsilyl silica column as the stationary phase (250 × 4 mm, 10 μm).

UV detection at 254 nm, a flow rate of 1 mL/min, and 20-μL injection volumes of the test

solutions (0.2 mg Monte/ml of 70% ethanol) were used. While for Domp tablets,

CHAPTER FIVE


methanol and 0.5% ammonium acetate in water were used as the mobile phases A and B,

respectively. A linear gradient elution with a flow rate of 1.5 ml/min was programmed as

follows: time 0 min: 30, 70, time 10 min: 100, 0, and time 12 min: 100, 0 for mobile

phases A and B, respectively. A based-deactivated, end capped L7 column was used as

the stationary phase (Hypersil C8 BDS, 100×4.6 mm, 3 μm). UV detection at 280 nm and

a 10-μL injection volume of the test solutions (5 mg Domp/ml of 0.1 M HCl in 50%

ethanol) were employed. The HPLC method was initially tested for system suitability

(i.e., peak symmetry, repeatability, and resolution) and for validation parameters (i.e.,

specificity, recovery, stability in solution, linearity, and limit of quantitation (LOQ))

according to USP guidelines [37].


5.3.1 Selection of process and ratio for co-processed chitin-mannitol excipient

In order to select the optimal ratio and process for co-processed excipient preparation,

three different ratios of chitin and mannitol (10:90, 20:80 and 30:70 w/w) and three

different processing techniques i.e., direct mixing, WG and RC were used. The prepared

excipients were lubricated with sodium stearyl fumarate (1.0% w/w) and compressed at

different tablet crushing forces (50 – 150 N). The tablets obtained were tested for

friability, disintegration and wetting times versus the corresponding crushing forces. The

preliminary results of the aforementioned experiments indicated that direct mixing and

WG were unsuitable, because the mixtures prepared by direct mixing displayed

unacceptable physical properties (e.g. poor flow and powder non-uniformity). The

difference in bulk densities of chitin (0.2 g/cm3) and mannitol (0.5 g/cm

3) is the reason

underlying such unacceptable physical properties. In the case of WG, the tablets suffered

from capping and high disintegration times due to the penetration of the dissolved

mannitol into the chitin pores. Such penetration did not allow the pores to act as as

functional compression and disintegration enhancers. However, RC gave reasonable

results. The data in Figure 5.1 shows the effect of crushing force on the friability,

disintegration and wetting times of tablets produced. Up to a crushing force of 90 N, all

chitin: mannitol ratios showed acceptable physical properties (low friability and fast

disintegration and wetting times). While at crushing forces above 90 N, the excipient

CHAPTER FIVE


prepared by using a chitin: mannitol ratio of 1:9 showed capping upon tablet compression

due to an insufficient amount of chitin, responsible for improving the compressibility.

Using ratios of chitin: mannitol of 2:8 and 3:7 (w/w) over all the investigated range of

crushing forces produced tablets with acceptable physical properties. However, a ratio of

chitin and mannitol of 2:8 (w/w) was chosen in order to obtain beneficial mannitol taste

properties and to reduce the amount of insoluble chitin in ODT preparations.

0

10

20

30

40

50

60

70

Dis

inte

gra

tio

n T

ime

(S

ec

)

Chitin: Mannitol (10:90)



a

Ta

ble

t ca

pp

ing

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Fri

ab

ility

(%

)

b

Ta

ble

t ca

pp

ing

Ta

ble

t ca

pp

ing

0

10

20

30

40

50

60

150120907050

We

ttin

g T

ime

(Se

c)

Crushing Force (N)

c

Ta

ble

t ca

pp

ing

Figure 5.1 Plots of the crushing force (N) versus (a) disintegration time, (b) friability,

and (c) wetting time for compacted mixtures prepared using different ratios of chitin and

mannitol (1:9, 2:8, and 3:7 w/w). Tablets were 10 mm in diameter and 250 mg in weight.

All powders were lubricated using 1% (w/w) sodium stearyl fumarate.

CHAPTER FIVE


5.3.2 Characterization of Cop-CM Powder

The FT-IR spectra of chitin, mannitol, the corresponding physical mixtures and co-

processed excipients (Cop-CM) are presented in Figure 5.2.

b

a

c

d

Wave number (cm1)

Tra

nsm

itta

nce

(A

.U.)

4000 3000 2000 1500 1000 500

Figure 5.2 FT-IR spectra of (a) mannitol, (b) chitin, (c) physical mixture of

chitin-mannitol (2:8, w/w), and (d) Cop-CM.

It is clear that the FT-IR of the physical mixture of chitin and mannitol (Figure 5.2c) is a

superposition of the vibrational band profiles contributed by chitin and mannitol

(Figures 5.2a and 5.2b). The dominance of the principal bands of mannitol in the physical

mixture is a result of its high fractional composition in the mixture (80% w/w). The two

bands in the 1550-1660 cm1

range corresponding to the chitin amide I and II vibrational

modes (Figure 5.2a) persist in the spectra of the physical mixture and Cop-CM, while the

remaining bands are due to mannitol. The absence of any shift in the FT-IR bands of the

Cop-CM (Figure 5.2d), in comparison with the bands of the physical mixture

(Figure 5.2c), suggests the absence of chemical interaction due to the use of RC to form

CHAPTER FIVE


the co-processed excipient Cop-CM.

Further analysis of the Cop-CM by XRPD (Figure 5.3) and DSC (Figure 5.4) techniques

showed the same results, where the signals corresponding to mannitol are dominant due

to its high percentage and crystallinity. The absence of new signals or shift in the patterns

indicates the absence of formation of a new crystal form or chemical interaction.

2

Inte

ns

ity (

A.U

.)

Figure 5.3 XRPD profiles of (a) mannitol, (b) chitin, (c) physical mixture of

chitin-mannitol (2:8, w/w), and (d) Cop-CM.

CHAPTER FIVE


Temperature (oC)

Hea

t fl

ow

(W

/g)

Temperature (oC)

He

at

flo

w (

Ex

oth

erm

ic)

Figure 5.4 DSC thermograms of (a) chitin, (b) mannitol, (c) physical mixture of chitin-

mannitol (2:8, w/w) and (d) Cop-CM.

SEM was used to investigate particle surface morphology (Figure 5.5). When comparing

the particle shape of mannitol (Figure 5.5a) with that of the Cop-CM (Figure 5.5d), it is

apparent that it has changed from rectangular rod granules to three-dimensional dense

compacts for the Cop-CM.

CHAPTER FIVE


a

b

c

d

Figure 5.5 SEM images of (a) mannitol, (b) chitin, (c) physical mixture of chitin-

mannitol (2:8, w/w), and (d) Cop-CM.

5.3.3 Physical Properties of Cop-CM Powder

The physical properties of the Cop-CM powders passed through two different mesh size

sieves (710 and 1000 m) were evaluated. The two powders have a water content of

about 1.5% w/w (DL38, Karl Fischer Titrator, Mettler, Switzerland) and a bulk density of

0.5-0.55 g/cm3 (SVM, Tapped volumeter, Erweka, Germany). The pH of a 5% (w/v)

aqueous dispersion is in the range 6-8. The particle size distribution (D10, D50 and D90)

of Cop-CM is given in Table 5.1.

CHAPTER FIVE


Table 5.1 The physical properties of Cop-CM.

Parameter Value

Water content (w/w%) 1.5

pH 6.0 – 8.0

Bulk density (gm/ml) 0.50-0.55

Tapped density (gm/ml) 0.55-0.65

Particle size distribution:

- Milling through 710µm

- Milling through 1000µm

D10: 5 µm; D50: 145 µm; D90: 496 µm

D10: 7 µm; D50: 170 µm; D90: 584 µm

Hausner’s ratio 1.13

Carr’s index 11.86

Angle of repose 32°

Particle size and shape are critical parameters in powder characterization, particularly in

DC formulations affecting powder performance, packing, consolidation, flowability and

compaction. It is one of the prime considerations in selecting excipients to develop and

optimize a pharmaceutical formulation. Ideally, DC excipients should exhibit narrow size

distributions with moderate-to-coarse particle size, having a mean particle size of 100 to

200 µm [38]. In ODT formulation, the control of particle size is essential for the water

insoluble excipients to minimize the grittiness feeling during the tablet administration.

Best results are obtained when using smaller particle size for insoluble excipients.

Another critical parameter for the DC excipient is the bulk density which can be used to

describe the packing behavior of granules [38]. Cop-CM powder passed through 710 µm

mesh size has a mean particle size of about 215 µm. A higher bulk density is

advantageous in tabletting because of a reduction in the powder-fill volume of the die.

Cop-CM powder sieved through 1000 µm mesh size has a bulk density of about 0.52

gm/mL and a tapped density of 0.59 gm/mL.

On the other hand, Hausner’s Ratio (H) is an indirect index of ease of powder flow. It is

calculated by using the formula, [25]

Η = TD/BD (2)

The simplest method of measurement of free flow of a powder is compressibility; an

CHAPTER FIVE


indication of the ease with which material can be induced to flow is given by Carr’s

Index (I) which is calculated using the formula:

I = 100 × (TD – BD)/ TD (3)

Hausner’s ratio of 1.0-1.11 indicates excellent flow whereas values of 1.12–1.18

indicate good flow, while Carr’s index of ≤10 indicates excellent flow, whereas I values

of 11-15 indicate good flow. (Generally lower Hausner’s ratio and Carr’s Index values

represent better flow).

The density change before and after tapping calculated as % compressibility (Carr’s

index) is an indicator of how fast granules can flow to their highest packing. The Carr’s

index calculated from the density data showed a value less than 12, and Hausner’s ratio

of less than 1.13 indicating further the good flowability, which is an important factor for

DC powders. Good flowability of powder is needed for content uniformity and less

weight variation in final tablets. According to US Pharmacopeia 31, General Chapter

<1174 >, angle of repose (25-30) indicates excellent flow, and 31-35 indicate good

flow. The Hausner`s ratio, Carr`s index and the angle of repose values for Cop-CM

powder are shown in Table 5.1. From the data obtained, Cop-CM powder showed a good

flow-ability and compressibility.

5.3.3.1 Moisture Uptake by Cop-CM

The data in Figure 5.6 shows the water uptake by Cop-CM and commercial ODT bases

(Phrmaburst C1, Isomalt 721, and Mannogem EZ) at 25oC and different relative

humidities.

CHAPTER FIVE


-1

14

29

44

59

45 55 65 75 85 95

% W

ater

Upta

ke


Isomalt 721

Pharmaburst C1

Mannogem EZ

Cop-CM

a

-1

2

5

8

11

14

45 55 65 75 85 95

% W

ater

Upta

ke


Isomalt 721

Pharmaburst C1

Mannogem EZ

Cop-CM

b

Figure 5.6 The water uptake by Cop-CM in comparison with some commercially

available ODT bases after incubation at 25oC and different relative humidity’s (a) for 2

weeks and (b) after equilibration at 25oC/45% relative humidity for one further day.

Up to 84% relative humidity for 2 weeks, all bases, except Pharmaburst C1, showed

insignificant increase in water uptake (Figure 5.6a). However, following equilibration for

1 day at 25oC/45% relative humidity, Pharmaburst C1 lost the excess water absorbed

(9%) to reach only 0.7% (Figure 5.6b). At high relative humidity (95%), the water uptake

follows the order: Cop-CM (8%) < Mannogem EZ (14%) < Pharmaburst C1 (46%) <

Isomalt galenIQTM

721 (66%). Following equilibration for 1 day at 25oC/45% relative

CHAPTER FIVE


humidity, all bases except Isomalt galenIQTM

721 lost the excess water absorbed to give

values less than 1% (Figure 5.6b). While it is about 14% for Isomalt galenIQTM

721

which is most probably due to partial dissolution of Isomalt at high relative humidity.

This difference in water uptake of different bases is due to the difference in their

components and their morphology (e.g. crystalline versus amorphous). The roller

compaction of large amount of mannitol (80% w/w) with chitin results in the coverage of

the outer surface of chitin with mannitol; therefore, the Cop-CM powder was clearly non-

hygroscopic due to the very minimal water uptake of mannitol.

5.3.3.2 Hygroscopicity of Tablets Prepared from Cop-CM

The water adsorption study was conducted for tablets prepared from Cop-CM at 75%

relative humidity and room temperature. Results indicate that the tablets prepared from

Cop-CM do not sorb water (less than 0.4% w/w). It is advantageous in the

pharmaceutical industry to have non-hygroscopic ODT preparations, as this will reduce

the cost of the expensive package which is usually used to obtain the required protection

against moisture.

5.3.3.3 Compression Profile of Tablet Prepared from Cop-CM

Data for the friability, disintegration and wetting times versus the corresponding crushing

force for tablets prepared using Cop-CM powders passed through either the 710 m or

1000 m sieves are shown in Figure 5.7. Generally, a reduction in particle size is

associated with an increase in tablet mechanical strength. The increase in mechanical

strength of the tablets is directly reflected in its physical properties (crushing force,

disintegration time, friability, wetting time, etc.) and attributed to an increase in the

surface area available for inter-particulate attraction [39]. However, when Cop-CM was

used it was found that varying the particle size had no impact on the tablet’s mechanical

strength. The mechanical strength of the tablets prepared from materials with a tendency

to fragment, such as mannitol, dibasic calcium phosphate dihydrate and saccharose

appear to be independent of particle size [40]. This could be the case for the Cop-CM

particles which contain excess amount of mannitol (80% w/w) and undergo

CHAPTER FIVE


fragmentation [41] at the early stages of compression, thereby causing a minimal effect

on tablet mechanical strength when varying the particle size.

0

50

100

150

200

250

300

Dis

inte

gra

tion

Tim

e (S

eco

nd

s)

0.05

0.15

0.25

0.35

0.45

0.55

0.65

Fri

abili

ty (

%)

Isomalt 721 +3% Crospovidone

Isomalt 721

Mannogem EZ + 3% Crospovidone

Cop-CM (sieved through 1000 micron)

Cop-CM (sieved through 710 micron)

Pharmaburst C1

Mannogem EZ

PanExcea MHC300G

0

60

120

180

240

300

360

Wet

ting

Tim

e (S

ec.)

Crushing Force (N)

> 3600 Sec > 3600 Sec> 3600 Sec

Figure 5.7 Plots of the crushing force (N) versus (a) disintegration time, (b) friability,

and (c) wetting time for tablets prepared from Cop-CM powders passed through either

710 m or 1000 m sieves in comparison with commercially available bases. The tablets

were 10 mm in diameter and 250 mg in weight. All samples were lubricated with 1%

(w/w) sodium stearyl fumarate.

CHAPTER FIVE


The disintegration time of ODTs is generally less than one minute and actual

disintegration time that patients expect is less than 30 seconds. The general compendial

method of performing disintegration tests for ODTs is not capable of detecting such a

very short disintegration time. The wetting time of the ODT is another important test,

which gives an insight into the disintegration properties of the tablet. Lower wetting time

indicates a quicker disintegration of the tablet [42]. With respect to tablet disintegration,

the Cop-CM showed a unique characteristic whereby tablet disintegration time was

independent of particle size and tablet crushing force (Figure 5.7). Tablets produced from

Cop-CM powders passed through either the 710 m or 1000 m sieves, at an upper

punch compression scale of 16-20 kN for each particle size, showed a superior

disintegration time ranging from 11.5 to 59 seconds and from 14 to 64 seconds,

respectively. This was achieved for tablet crushing force values ranging from 50-150 N.

By increasing the crushing strength from 50 to 150 N, the wetting time of the tablet was

only increased from 9 to 35 seconds. This suggests that capillary action is the dominant

mechanism for the disintegration of Cop-CM which is irrespective of the tablet crushing

force [23]. In addition, the inter-particulate voids within the chitin particles in the

Cop-CM, as previously mentioned, remain intact and unchanged after using the RC

procedure with mannitol and by varying the powder particle size. Regarding powder

compressibility, chitin within the Cop-CM mixture provides an effective means of

obtaining hard tablets with low friability while persisting in its fast disintegration and

wetting properties, as can be concluded from the data shown in Figure 5.7.

Four commercially available ODT excipients were used for comparison purposes

including, Isomalt galenIQTM

721, Mannogem EZ, Pharmabust EZ and PanExcea

MHC200G. The data in Table 5.2 shows the function and composition of these

excipients. Crospovidone (a cross-linked polymer of N-vinyl-2-pyrrolidinone is often

used at concentrations up to 5.0% and is commonly used as an effective disintegrant in

tablet formulations) is used at 3% w/w level in both Isomalt galenIQTM

721 and

Mannogem EZ powders [11]. Both PanExcea MC200G and Pharmaburst C1 already

contain disintegrant in their compositions (calcium silicate and crospovidone,

respectively).

CHAPTER FIVE


Table 5.2 Function and composition of used ODT excipients.

Trade Name Composition Manufacturer Advantages &

Function

PanExcea

MC200G

Mannitol (75%),

calcium silicate

(25%).

Particle size: 50%

(103μm)

Avantor Performance Materials,

Inc./USA

http://www.avantormaterials.com/

High performance,

rapid disintegration,

direct compression

excipient for oro-

dissolving tablets

formulation

MannogemTM

EZ

Spray dried direct

compression mannitol

Particle size: 60%

(75-150μm)

SPI Pharma TM, Inc., New Castel ,

U.S.A

http://www.spipharma.com

Assist in

formulating

difficult to use

non-hygroscopic

ODT containing

fine APIs

Pharmaburst TM

C1

Mannitol 84%,

crospovidone 16%,

silicon dioxide <1%

High

compactibility, high

loading in small

diameter tablets,

smooth mouth feel,

rapid disintegration

Isomalt galenIQ-

721

1-O--D-

glucopyranosyl-D-

mannitol dehydrate

and

6-O--D-

glucopyranosyl-D-

sorbitol (1:3)

Particle size: 90%

(360μm), 50% (220

μm)

BENEO-Palatinit GmbH (Germany)

http://www.beneo-

palatinit.com/en/Pharma_Excipients

/galenIQ/galenIQ_Grades/galenIQ721/

Highly soluble

agglomerated

spherical isomalt

for fast dissolving

and very fast

disintegrating direct

compression tablet

preparations

CHAPTER FIVE


In order to obtain a tablet crushing force range of 50-150 N, upper punch compression

scales of 25.5 to 29.5 kN were applied to all excipients except for PanExcea in which

case a scale range from 39-42 kN was applied. For all reference excipients used,

increasing the crushing force from 50 to 150 N resulted in the disintegration and wetting

time of the tablets increasing linearly. The friability of the tablets was found to be within

the limit (less than 0.7% for Isomalt galenIQTM

721+3% crospovidone) at the lower

crushing force (50 N). With increasing tablet crushing force, the friability was

significantly reduced (less than 0.2%). At 50 N tablet crushing force value, the reference

excipients except for Mannogem EZ and Isomalt galenIQTM

721 (with and without

crospovidone) gave a disintegration time of less than 30 seconds. In addition, the wetting

time for all reference excipients was less than 30 seconds at the same crushing force. The

data in Figure 5.7 clearly shows that by increasing the tablet crushing force, the

disintegration times and wetting times were increased accordingly. Only, Isomalt

galenIQTM

721 plus crospovidone and PanExcea MC200G tablets showed a short

disintegration time (less than 33 seconds) at the highest crushing force (150 N), whereas

for the other excipients a disintegration time range of 120-300 seconds were observed. At

a tablet crushing force of 150 N, only pharmaburst C1 and Mannogem EZ plus

crospovidone showed a short wetting time of less than 60 seconds (52 and 16 seconds,

respectively).

It can be clearly observed that with Cop-CM, the increasing in tablet crushing force up to

150 N does not significantly affect both disintegration and wetting times. This property is

extremely advantageous where very fast disintegrating hard tablets can be prepared using

Cop-CM and simply packed in traditional packaging materials. This prevents the need of

a special type of packaging to avoid the breakage of the tablets during removal from the

package. MannogemTM

EZ + 3% crospovidone combination has showed similar behavior

to Cop-CM at high tablets crushing forces. At 150 N tablet crushing force, PanExcea

MHC300G has preserved the very short disintegration time, while the tablet wetting time

was significantly increased. On the otherwise, Pharmaburst C1 behave in a different

manner, where by increasing the tablet crushing force to 150 N the disintegration time

was relatively high (> 2 min), while the tablets wetting time was not significantly

affected.

CHAPTER FIVE


5.3.3.4 Powder Compressibility

The Kawakita equation (Equation 4) is used to study powder compression using the

degree of volume reduction, C. The basis for the Kawakita equation for powder

compression is that particles subjected to a compressive load in a confined space are

viewed as a system in equilibrium at all stages of compression, so that the product of the

pressure term and the volume term is a constant [31]:

bP

abP

V

VVC o

1

)(

0

(4)

Where, Vo is the initial volume and V is the volume of powder column under an applied

pressure, P. The constants a and b represent the minimum porosity before compression

and plasticity of the material, respectively. The reciprocal of b defines the pressure

required to reduce the powder bed by 50% [32, 33]. Equation 4 can be re-arranged in

linear form as:

aba

P

C

P 1 (5)

The expression for particle rearrangement can be affected simultaneously by the two


product of the Kawakita parameters a and b, may hence be used as an indicator of particle

rearrangement during compression [34]. Figure 5.8 shows the Kawakita plots for

mannitol, Cop-CM and chitin.

CHAPTER FIVE


y = 1.736x + 17.932R² = 1

y = 1.5121x + 16.88R² = 0.9998

y = 1.2228x + 12.927R² = 1

0

100

200

300

400

500

600

700

800

50 100 150 200 250 300 350 400 450 500

P/C

Pressure (MPa)

Mannitol

Cop-CM

Chitin

Figure 5.8 Kawakita plot for Cop-CM. Tablets were 12 mm in diameter and 400 mg in

weight.

The Kawakita constants a, b, ab and 1/b were calculated from the intercept and slope of

the plots (Table 5.3).

Table 5.3 Kawakita parameters for mannitol, chitin and Cop-CM.

Material Kawakita parameters

Slope Intercept a ab b 1/b

Mannitol 1.736 17.932 0.576 0.0558 0.0968 10.330

Chitin 1.223 12.927 0.818 0.0774 0.0946 10.570

Cop-CM* 1.512 16.880 0.661 0.0592 0.0896 11.164

*Cop-CM represents the co-processed chitin-mannitol (2:8 w/w) mixture

The constant a, which represents the compressibility, is the highest for chitin (a = 0.818)

and this is due to the high internal surface pores. The compressibility of Cop-CM is

significantly higher than mannitol alone (a = 0.661 and 0.576, respectively) and this is

ascribed to the addition of the chitin to mannitol. This result emphasizes the fact that

although the mannitol constitutes 80% of the Cop-CM content, using RC techniques in

CHAPTER FIVE


the preparation of the Cop-CM keeps the large chitin surface pores active and unoccupied

because mannitol physically adheres at the outer chitin surfaces.

The increase in the ab value for Cop-CM (0.0592), which is a measure of the extent of

particle rearrangement, indicates that the addition of chitin has improved the degree of

particle rearrangement and packing during tabletting. The 1/b parameter is an inverse

measure of the amount of plastic deformation occurring during the compression process

[22, 43]. Generally, the low value of 1/b is a reflection of the soft nature of the material

and that the material is readily deformed plastically under pressure [44].

Chitin is a highly porous material and forms intermolecular hydrogen bonds between

adjacent plastic deformed chitin particles. The presence of moisture within the porous

structure of chitin enforces the formation of hydrogen bond bridges which increase the

internal binding upon compaction. Therefore, the use of a smaller amount of chitin (20%)

with mannitol within the Cop-CM decreases plastic deformation during compression [22,

45].

5.3.3.5 Loading Capacity

The loading capacity of Cop-CM excipient was studied by using metronidazole as a

model for an incompressible material. Compressing metronidazole alone (100% as a

reference) gives rise to tablets with low mechanical strength and long disintegration time.

However, the effect of increasing the weight ratios of Cop-CM/metronidazole from 0/500

to 500/0 (wt/wt) on these properties were investigated. The results indicated that by

increasing the quantity of the Cop-CM in the matrix, the compactability is significantly

improved and the disintegration time is decreased as shown Figure 5.9. As a result

Cop-CM is capable to accommodate poorly compressible APIs with high loading

capacity without significantly affecting the physical and mechanical properties.

CHAPTER FIVE


-50

50

150

250

350

450

550

650

750

850

950

1050

1150

1250

1350

1450

1550

1650

1750

1850

0

10

20

30

40

50

60

70

80

90

100

110

0-500 50-450 150-300 250-250 350-150 450-50 500-0

Dis

inte

gra

tio

n T

ime

(S

ec

.)

Ta

ble

t C

rus

hin

g F

orc

e (

N)

Excipient: Metronidazole Ratio (mg:mg)

Metronidazole:Cop-CM

Metronidazole:(Treated Physical Mixture of Chitin and mannitol) Disintegration Time (sec) Cop-CM

Disintegration Time (sec) (Physical Mixture of Chitin-Mannitol)

Figure 5.9 Relationship between tablet crushing force and disintegration time at different

Cop-CM: metronidazole ratios using a physical mixture of chitin-mannitol (2:8, w/w) as a

reference. Data are represented as the mean of n = 10.


The functionality of the Cop-CM as an excipient was investigated by examining different

processing techniques including DC, RC and WG to prepare tablets. The three

formulations containing Cop-CM and low strength APIs (Monte and Domp) were

investigated. The performance and mechanical properties of the prepared tablets were

examined and the results are summarized in Table 5.4.

CHAPTER FIVE


Table 5.4 Composition and physical properties of Monte and Domp ODTs.

Materials Composition (% w/w)

Monte Domp

API 01.77 03.40

Cop-CM 94.73 93.10

Strawberry powder flavor 02.00 02.00

Aspartame 00.50 00.50

Sodium stearyl fumarate 01.00 01.00

Tablet Physical Properties Tablet preparation process

DC RC WG DC RC WG

Crushing force (N) 70 – 80 60 – 70

Friability (%) 0.25 0.32 0.30 0.18 0.29 0.37

Disintegration time(sec) 20 30 20 26 20 28

The tablets obtained from all the processing techniques showed high internal binding

(crushing force: 60-80 N and friability: < 0.4%) and fast disintegration times (≤ 30 sec).

The results indicate that Cop-CM is compressible and preserved its functionality whether

utilized in DC, RC or WG formulations. Hence, it can be used as a multi-functional base

(binder, filler and disintegrant) in ODT formulations.

5.3.3.7 Stability Studies

The stability of Monte and Domp tablets prepared by RC procedures in the functionality

section was investigated. Tablets were packed in aluminum/aluminum blisters and

incubated at 25oC and 40

oC/75% relative humidity for different periods of time and then

tested by HPLC methods. The HPLC method was initially tested for system suitability

(i.e., peak symmetry, repeatability, and resolution) and for validation parameters (i.e.,

specificity, stability in solution, linearity and limit of quantitation (LOQ)) according to

USP and ICH guidelines [37, 46]. The HPLC results showed a good separation between

the APIs and their related impurities. Also the methods were found to be suitable for

stability studies, i.e., the resolution, tailing factors and injection repeatability are within

CHAPTER FIVE


the acceptable criteria. In addition, analysis of samples obtained from stress-testing

studies in solutions (0.1N NaOH, 0.1N HCl, and 0.3% H2O2) indicated that the HPLC

methods are stability indicating. The methods were linear over the range of ±50% of the

target concentrations with r2 of > 0.99. The LOQ values are within 0.08 – 0.4 and 0.05 –

0.14 (w/w %) for Monte and Domp tablets, respectively.

As shown in the data in Table 5.5, no significant decrease in the potency of Monte and

Domp tablets occurred upon storage at 40C/75% RH for 6 months. Monte is liable to

oxidation by heat [35] forming Monte S-oxide; however, under shelf-life conditions the

degradation content of this product is within the limit (2.0%). Domp tablets display

excellent stability when the fraction of impurities does not exceed 0.1% after 6 months

incubation at 40oC/75% RH. Both products showed fast disintegration (< 30 sec) and a

drug release (> 90%) before and after incubation at 40oC/75% RH indicating the absence

of formulation ageing (Table 5.5).

Table 5.5 Stability data for Monte and Domp tablets.

Product Compound/Limit

Percentage (w/w)

25oC 40

oC/75% RH

Initial 24 months 3 months 6 months

Monte

Monte/90% - 110% 99.4 104.8 102.8 98.2

Monte S-oxide/≤2.0% 0.9 1.1 3.4 3.6

Monte cis-isomer/≤0.5% 0.1 0.5 0.1 0.1

Any other≤0.4% 0.0 0.2 0.1 0.1

Total impurities≤3.0% 1.0 2.0 3.6 3.8

Domp

Domp/95%-105% 100.1 - 100.7 101.4

Any other/≤0.25% 0.06 - 0.04 0.04

Total impurities/≤0.5% 0.2 - 0.1 0.1

CHAPTER FIVE


5.4 Conclusions

Co-processing of crystalline mannitol with -chitin by RC offers an excellent multi-

functional base for ODT formulations. The novel excipient displayed fast disintegration

and wetting properties over a wide range of tablet crushing force values in comparison

with commercially available ODT bases. Regardless of the preparation method (DC, WG

or DG), the functionality of the novel excipient was preserved. Moreover, the excipient

can accommodate a high amount of API without affecting its functionality. Utilization of

the novel excipient in ODT containing active pharmaceutical ingredients, offers very fast

disintegration and wetting rates, excellent chemical stability and binding properties.

Consequently, the use of expensive packaging materials for ODT can be eliminated as the

tablets are not prone to breakage when used by patients.

CHAPTER FIVE


5.5 References

[1] M. Jivraj, L.G. Martini, C.M. Thomson, An overview of the different excipients useful

for the direct compression of tablets. Pharm. Sci. Tech Today. 3 (2000) 58–63.

[2] L. Bhattacharyya, S. Shuber, S. Sheehan, R. William, Chapter 1, Excipients:

background/Introduction, in: A. Katdare and M.V. Chaubal (Eds.), Excipient

development for pharmaceutical, biotechnology, and drug delivery systems, Informa

Healthcare USA, Inc., New York, 2006.

[3] N. Jonwal, P. Mane, S. Mokati, A. Meena, Preparation and in vitro evaluation of

mouth dissolving tablets of domperidone, Int. J Pharm. Pharm. Sci. 3 (2010) 975-

1491.

[4] Guidance for industry: Orally disintegrating tablets. U.S. Department of Health and

Human Services, Food and Drug Administration, Centre for Drug Evaluation and

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[5] Orodispersible tablets, European Pharmacopeia Vol. 1 (Edition 7.0), Jan. 2011. p: 737.

[6] Polyplasdone® crospovidone: Superdisintegrants for orally disintegrating and

chewable tablets, 15 February 2012 <http://www. isppharmaceuticals.com/

Literature/ISP-PH5284PolyplasdoneODTSheetVF.pdf>.

[7] K.B. Deshpande, N.S.Ganesh, Formulation and evaluation of orodispersible tablets of

propranolol hydrochloride, Int. J. Res. Pharm. Biomed. Sci. 2 (2011) 529-534.

[8] S. Bandari, R.K. Mittapalli, R. Gannu, Y.M. Rao, Orodispersible tablets: An

overview, Asian J. Pharm. 2 (2008) 2-11.

[9] W.R. Pfister, T.K. Ghosh, Orally disintegrating tablets, products, technologies, and

development issues. Pharmaceutical Technology, 15 February 2012

<http://pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=185957>.

[10] S. Schiermeier, P.C. Schmidt, Fast dispersible ibuprofen tablets, Eur. J. Pharm. Sci.

15 (2002) 295–305.

[11] C.R. Raymond, J.S. Paul and C.O. Siân, Handbook of pharmaceutical excipients, 5th

Edition, Pharmaceutical Press, Greyslake IL, London and American Pharmacists

Association, Washington, DC, 2006.

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CHAPTER FIVE


[12] Excipients and carriers: “Mannogem EZ” spray dried mannitol, 15 February 2012

http://www.spipharma.com/default.asp?contentID=639.

[13] L. Dolson, Low Carb Diets: What are sugar alcohols? Comparisons and blood sugar

impact, 15 February 2012 <http://lowcarbdiets.about.com/od/whattoeat/a/

sugaralcohols.htm>.

[14] M. Jivraj, L.G. Martini, C.M. Thomson, An overview of the different excipients

useful for the direct compression of tablets, PSTT 3 (2000) 85-63.

[15] L. Erik, L. Philippe, L. Jose, Pulverulent mannitol and process for preparing it, U.S.

Patent 6743447 (2004).

[16] B. Debord, C. Lefebvre, A.M. Guyothermann, J. Hubert, R. Bouche, J.C. Guyot,

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compression, Drug Dev. Ind. Pharm. 13 (1987) 1533-1546.

[17] Excipients and Carriers: “Mannogem” Mannitol, 15 February 2012,

http://www.spipharma.com/default.asp?contentID=597.

[18] N.H. Daraghmeh, B.Z. Chowdhry, S.A. Leharne, M.M. Al Omari, A.A. Badwan,

Chitin, in: H. Brittain (Ed.). Profiles of drug substances, excipients and related

methodology, Volume 36, Elsevier Inc., N.Y., 2011.

[19] R.A.A. Muzzarelli, Chitin, Oxford, Pergamon, 1977.

[20] P. Gupta, S.K. Nachaegari, A.K. Bansal, Improved excipient functionality by co-

processing, in: A. Katdare, M.V. Chaubal (Eds.), Excipient development for

pharmaceutical, biotechnology, and drug delivery systems, Informa Healthcare, New

York, London, 2006.

[21] I. Rashid, N. Daraghmeh, M. Al-Remawai, S.A. Leharne, B.Z. Chowdhry, A.

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Pharm. Sci. 98 (2009) 4887–901.

[22] I. Rashid, M. Al-Remawi, A. Eftaiha, A. Badwan, Chitin–silicon dioxide

coprecipitate as a novel superdisintegrant, J. Pharm. Sci. 97 (2008) 4955–69.

[23] N. Daraghmeh, I. Rashid, M.M.H. Al Omari, S.A. Leharne, B.Z. Chowdhry, A.

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and crystalline mannitol, AAPS Pharm.Sci.Tech. 11, (4) (2010).



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[24] N.H. Daraghmeh, M.M. Al Omari, A.A. Badwan, Pharmaceutical excipient, method

for its preparation and use thereof. EP Patent EP2384742 (2011).

[25] M.Pr. Khinchi, M.K. Gupta, A. Bhandari, N. Sharma, D. Agarwal, Design and

development of orally disintegrating tablets of famotidine prepared by direct

compression method using different superdisintegrants, J. App. Pharm. Sci. 1 (2011)

50-58.

[26] R.C. Weast, Handbook of chemistry and physics, 55th Edition, CRC Press; 1974–

1975, pp. E-46.

[27] Disintegration, friability of uncoated tablets, resistance to crushing of tablets, British

pharmacopeia, London: The Stationary Office. Volume IV, Appendixes XIIA, XVII G

and H; 2008. pp. A283, A423, A424.

[28] Dissolution <711>, United States Pharmacopeia and National Formulary (USP32-

NF27), Rockville, MD, US Pharmacopoeia Convention, Volume 1, 2009. pp. 263-271.

[29] Dissolution method. U.S. FDA, Rockville. 2010, 15 February 2012 <http://www.

accessdata. fda.gov/scripts/cder/dissolution/index.cfm>.

[30] Dissolution, disintegration, friability of uncoated tablets, resistance to crushing of

tablets, British pharmacopeia, London, The Stationary Office, Volume IV, Appendixes

XIIA, XVII G and H; 2008. p. A283, A423, A424.

[31] K. Kawakita, K.H. Lüdde, Some considerations on powder compression equations,

Powder Technol. 4 (1971) 61–68.

[32] P. Shivanand, O.L. Sprockel, Compaction behaviour of cellulose polymers, Powder

Technol. 69 (1992) 177–184.

[33] C. Lin, T. Cham, Compression behaviour and tensile strength of heat-treated

polyethylene glycols, Int. J. Pharm. 118 (1995) 169–179.

[34] J. Nordström, I. Klevan, G. Alderborn, A particle rearrangement index based on the

Kawakita powder compression equation, J. Pharm. Sci. 98 (2008) 1053-1063.

[35] M.M. Al Omari, R.M. Zoubi, E.I. Hasan, T.Z. Khader, A.A. Badwan, Effect of light

and heat on the stability of montelukast in solution and in its solid state, J. Pharm.

Biomed. Anal. 45 (2007) 465-471.

[36] A.A. Badwan, The Jordanian pharmaceutical manufacturing Co. (JPM), Jordan,

Unpublished data (2012).

CHAPTER FIVE


[37] Validation of compendia procedures <1225>, United States pharmacopeia and national

formulary (USP32-NF27), Rockville, MD, US Pharmacopoeia Convention, Volume I,

2009, pp. 733-736.

[38] Glenn T. Carlson and Bruno C. Hancock. A Comparison of physical and mechanical

properties of common tableting diluents. . In: Katdare A, Chaubal MV, editors.

Excipient development for pharmaceutical, biotechnology, and drug delivery systems.

New York, London: Informa healthcare; 2006.

[39] C. Nyström, G. Alderborn, M. Duberg, P-G. Karehill, Bonding surface area and

bonding mechanism-two important factors for the understanding of powder

compactibility, Drug Dev. Ind. Pharm. 19 (1993) 2143-2196.

[40] G. Alderborn, E. Börjesson, M. Glazer, C. Nyström, Studies on direct compression of

tablets. XIX: The effect of particle size and shape on the mechanical strength of sodium

bicarbonate tablets, Acta Pharm. Suec. 25 (1988) 31-40.

[41] A.M. Juppo, Change in porosity parameters of lactose, glucose and mannitol

granules caused by low compression force, Int. J. Pharm. 130 (1996) 149–157.

[42] D. Bhowmik, B. Chiranjib, Krishnakanth, Pankaj, R.M. Chandira. Fast dissolving

tablet: An overview, J. Chem. Pharm. Res. 1 (2009) 163-177.

[43] O.A. Adetunji, M.A. Odeniyi, O.A. Itiola, Compression, mechanical and release

properties of chloroquine phosphate tablets containing corn and trifoliate yam

starches as binders, Trop. J. Pharm. Res. 5 (2006) 589-596.

[44] E. Martins, I. Christiana, K. Olobayo, Effect of grewia gum on the mechanical

properties of paracetamol tablet formulations. African J. Pharm. Pharmacol. 2 (2008)

1-6.

[45] Y. Zhang, Y. Law, S. Chakrabarti, Physical properties and compact analysis of

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[46] European Medicines Agency, Validation of Analytical Procedures: Text and

Methodology, 15 February 2012 http://www.emea.europa.eu/docs/en_GB/

document_library/Scientific_guideline/2009/09/WC500002662.pdf

CHAPTER SIX


6. SUMMARY AND FUTURE WORK

6.1 Summary

The hypothesis that, despite being highly porous and displaying low compactibilty, guest

molecules such as metal silicates or mannitol can be accommodated in the chitin pores

via relatively simple co-processing procedures has been proved by the work reported in

this thesis. The foregoing was clearly shown by the high compactibility and crushing

force data obtained for the pharmaceutical tablets prepared by using the chitin-metal

silicates and chitin-mannitol co-processed excipients. Additionally it is to be noted that

the tablets maintained their high crushing force and internal binding; the fast

disintegration and wettability characteristics were also preserved. The functionality,

compatibility and stability of the co-processed chitin excipients were also investigated

and evaluated using problematic active pharmaceutical excipients. The results obtained

showed the multi-functionality and suitability of the prepared excipients in improving the

physical and chemical properties of the prepared tablets.

6.1.1 Characterization of Chitin–Metal Silicates as Binding Super-Disintegrants

The modification of chitin (a plastic material), as a selected hydrophilic polymer, using

different metal silicates (brittle materials) e.g., aluminium, calcium and magnesium has

resulted in the production of a non-hygroscopic multifunctional excipient with superior

super-disintegration and binding properties. The interaction of chitin with metal silicate

excipients does not involve a chemical interaction, as shown by analysis of IR and XRPD

data. Disintegration and binding properties for the tablets produced using this excipient

were also found to be independent of particle size and applied compression force.

Aluminium obviously cannot be used because of e.g. neuronal toxicity. Calcium

increases the pH of the resulting chitin-metal silicate excipient to a pH of 10.5 which is

not suitable for most APIs, as it is highly basic. Therefore magnesium silicate was the

best candidate amongst the metal silicates for co-processing with chitin. The functionality

of the chitin-Mg silicate co-processed excipient was assessed by formulating different

APIs including paracetamol, mefenamic acid and gemfibrozil using direct compression as

well as wet and dry granulation preparation techniques. Chitin-Mg silicate preserved its

CHAPTER SIX


functionality, whereby it’s binding and superdisintegration properties remained

unaffected by high concentrations of poorly compressible APIs using different

preparation methods. The physical properties and drug dissolution profile of the

ibuprofen/chitin-Mg silicate tablet matrix were found to be unaffected even when 5%

(w/w) lubrication was performed using a powerful lubricant such as MgSt. Also similar

drug dissolution was attained for gemfibrozil tablets using 3% (w/w) MgSt when

compared to a reference (LOPID®

tablets). This indicates that lubrication has a minimal

effect on the chitin-metal silicate tablet matrix.

6.1.2 Characterization of the Impact of Magnesium Stearate Lubrication on the

Tabletting Properties of Chitin-Mg Silicate as a Super-Disintegrating Binder

When Compared to Avicel® 200

Lubricants are vital excipients in tablet formulation. Magnesium stearate is one of the

most widely used excipients due to its high melting point, efficiency and economy.

Magnesium stearate reduces tablet hardness and prolongs drug release due to its

hydrophobicity. Thorough mixing of an active pharmaceutical ingredient with

magnesium stearate may result in some sort of interaction and thus the ability of powder

to form tablets is time dependent. Therefore, investigations were conducted to study the

effects of lubrication on the functionality and performance of chitin-metal silicates. As a

model, chitin-Mg silicate was selected from amongst the other metal silicates and

magnesium stearate was used as a lubricant. Avicel® 200 (commercially available

microcrystalline cellulose with an average particle size of 180 µm) was used as the direct

compression reference excipient. Microcrystalline cellulose is similar in chemical

structure to chitin, where the acetyl group of chitin is replaced with a hydroxyl moiety.

The co-precipitation of magnesium silicate on chitin and Avicel

was clearly beneficial

in minimizing the deleterious effects of MgSt. The addition of MgSt as a lubrication aid

did not show a significant variation in disintegration, dissolution, and crushing strength of

compacts made from chitin-Mg silicate. Such variation was clearly observed when a

comparison was made with Avicel® 200. This is due to the smooth irregular, folded

particle shape of chitin which results in a high surface area capable of holding/adsorbing

a high amount of lubricant in its surface pores. Co-precipitation with magnesium silicate

CHAPTER SIX


changes Avicel® 200 into a less lubricant sensitive excipient with regard to compaction

and binding properties, whilst the disintegration time of tablets prepared remains high.

6.1.3 Preparation and Characterization of a Novel Co-Processed Excipient of

Chitin and Crystalline Mannitol

Chitin is well known as a disintegrant and filler in tablet and capsule formulation because

of its unique properties (chemically inactive, naturally abundant, biodegradable,

non-toxic material). α-Chitin is a highly compressible material due to its high surface

porous structure, but the compaction and binding properties of chitin need to be

improved. Mannitol, a water soluble sugar alcohol, was used in order to improve the

binding properties of chitin. It is a non-hygroscopic material commonly known as a

“potential excipient” since it is compatible with the majority of pharmaceutical active

ingredients. Unfortunately, crystalline mannitol is friable with limited flow properties and

poor solubility when compared to lactose and other sugars. A small amount of mannitol

(< 30% w/w) was physically co-processed with chitin using different methods. The wet

granulation processing of chitin and mannitol mixture (80:20) resulted in a

non-hygroscopic valuable multi-functional excipient in terms of disintegration and

compaction properties. The tablets prepared from the Cop-MC displayed a fast

disintegration time while maintaining their superior binding properties. Different APIs

were incorporated in tablets consisting of Cop-MC and the lubricant. Results showed the

high stability of the APIs in a Cop-MC matrix.

6.1.4 A Novel Oro-Dispersible Tablet Base: Characterization and Performance

ODT tablets need to exhibit rapid disintegration/dissolving effects; therefore high levels

of superdisintegrants (up to 10-20 % (w/w)) are usually added to achieve this target.

Accordingly ODTs are packed in unit dose special type blisters due to their low hardness

and high friability. Additional excipients including filler, binder, lubricant, sweetener,

and colouring material can be added to improve the “elegance” and identification of the

ODTs. Mannitol is widely used in ODT formulations because of its unique properties

(non-hygroscopic, sweet, smooth and cool taste feel). Therefore it was advantageous, for

a material like mannitol to be combined with a highly porous disintegrant/filler such as

CHAPTER SIX


chitin via a physical co-processing methodology to improve its compaction and

disintegration properties. Roll compaction was found to be a suitable preparation method,

where optimal physical properties were obtained for the co-processed excipient.

Co-processed mixtures of chitin (20 and 30% w/w) with mannitol show excellent binding

properties, fast disintegration and wetting properties upon tablet compression. Further

studies were performed on the co-processed mixture of mannitol and chitin at a ratio of

80:20 (Cop-CM), including functionality, compression profile, hygroscopicity and

loading capacity. Results indicate that the non-hygroscopic excipient is functional when

different tablet preparation procedures are used by maintaining the overall excellent

physical properties of the tablets produced. The disintegration and wetting properties of

Cop-CM are not significantly affected by increasing the crushing force of the tablets

which allow the formulator to produce hard ODTs with fast disintegration and wetting

times. The foregoing will permit the use of blister packaging without the need for

specialised packaging procedures.

6.2 Future Work

Metal silicates, via co-precipitation in the pores and surface of chitin are potentially

useful single multifunctional excipients. The co-processed excipient acts as both a binder

and filler while maintaining its superdisintegrating properties and it was successfully used

in formulating hard tablets with super-disinitegration properties.

Among the sugar alcohols, crystalline mannitol was used for co-processing with chitin

because of its inert and unique properties. Two different excipeints were prepared by the

co-processing of chitin with mannitol. The first excipient (Cop-MC) was developed with

80% w/w chitin where it can be used successfully used as multifunctional excipient in the

preparation of immediate tablet dosage form. The second excipient (Cop-CM) was

designed with 80%w/w mannitol to serve as a multifunctional ODT base.

The following research is aimed at providing recommendations for further work, based

on results and observations obtained from co-processing chitin with mannitol and metal

silicates. It is important to investigate the modification of chitin properties using materials

other than silicates and mannitol to obtain additional co-processed excipients which can

can be used in a wide spectrum of pharmaceutical applications and dosage forms in terms

CHAPTER SIX


of physical properties, suitability and compatibility. Other sugar alcohols including

sorbitol, erthritol, xylitol, maltitol and lactitol need to be investigated for their suitability

in formulating fast disintegrating and chewable tablets.

6.2.1 Determination of Degree of Deacetylation in Chitin

Most of the methods available for the analysis of degree of deacetylation of chitin are

complicated and time consuming (e.g, NMR, XRPD, mass spectroscopy, differential

scanning calorimetry and FTIR). However, the aforementioned instruments are not

always available. In addition most of the current methods rely upon the degradation of

chitin and this may lead to incorrect results. Therefore, the non-aqueous potentiometric

titration of the reactive amine groups of chitin may be possible using saturated calcium

chloride di-hydrate in methanol as a solvent. In addition the spectrophotometric method

could have potential using the same solvent system by acquiring 1st

derivative spectra.

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